CS268841B2 - Method of optically active(-)-oxabicyclo/3,3,0/octanoles production - Google Patents
Method of optically active(-)-oxabicyclo/3,3,0/octanoles production Download PDFInfo
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- CS268841B2 CS268841B2 CS878150A CS815087A CS268841B2 CS 268841 B2 CS268841 B2 CS 268841B2 CS 878150 A CS878150 A CS 878150A CS 815087 A CS815087 A CS 815087A CS 268841 B2 CS268841 B2 CS 268841B2
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- oxabicyclo
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 108091005804 Peptidases Proteins 0.000 claims description 4
- 239000004367 Lipase Substances 0.000 claims description 3
- 102000004882 Lipase Human genes 0.000 claims description 3
- 108090001060 Lipase Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 235000019421 lipase Nutrition 0.000 claims description 3
- 102000035195 Peptidases Human genes 0.000 claims description 2
- 102000005158 Subtilisins Human genes 0.000 claims description 2
- 108010056079 Subtilisins Proteins 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 230000000707 stereoselective effect Effects 0.000 abstract 1
- RHLVCLIPMVJYKS-UHFFFAOYSA-N 3-octanone Chemical compound CCCCCC(=O)CC RHLVCLIPMVJYKS-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000003815 prostacyclins Chemical class 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- AHXADOAHIKYQRT-UHFFFAOYSA-N 2,5-dimethylheptan-4-one Chemical compound CCC(C)C(=O)CC(C)C AHXADOAHIKYQRT-UHFFFAOYSA-N 0.000 description 1
- IVIIJFDZEUPSLZ-UHFFFAOYSA-N 3-cyclooctyl-3-hydroxyoxocan-2-one Chemical class C1CCCCCCC1C1(O)CCCCCOC1=O IVIIJFDZEUPSLZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- DXVYLFHTJZWTRF-UHFFFAOYSA-N Ethyl isobutyl ketone Chemical compound CCC(=O)CC(C)C DXVYLFHTJZWTRF-UHFFFAOYSA-N 0.000 description 1
- 241000193317 Lindra <fungus> Species 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical class O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Biochemistry (AREA)
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- Genetics & Genomics (AREA)
- Analytical Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
Description
CS 26SS41 32CS 26SS41 32
Vynález ее týká způsobu etereospecifleká hydrolýzy acylátu raceeických 7c<-acyloxy•6β-hydroxymethyl-2-oxabicyklo [з,3,$ okatan-3-onů poeocí enzyaů za vzniku odpovídajících opticky aktivních alkoholů» tj. opticky aktivních (-)-oxablcyklo- ^3»3eoJ oktanolonů.The present invention also relates to a process for the ether-specific hydrolysis of racemic acyl 7-α-acyloxy-6β-hydroxymethyl-2-oxabicyclo [2.3.1] octatan-3-ones by enzymes to form corresponding optically active alcohols, i.e. optically active (-) - oxabicyclo- ^ 3 »3 oJ oktanolonů e.
Postup podle vynálezu je zvláště vhodný к výrobě opticky aktivních (-)-oxablcyklo [з»3.о] oktenolonů obecného vzorce (-)-XThe process according to the invention is particularly suitable for the production of optically active (-) - oxablicyclo [з »3.о] octenolones of the general formula (-) - X
ve které·in which·
R znamená ato· vodíku nebo zneaená skupinu vzorceR represents a hydrogen atom or an unsaturated group of the formula
přičeažpřičeaž
R| znaeaná atom vodíku» alkylovou skupinu e 1 až 7 etoay uhlíku nebo fenylovou skupinu. Tento postup spočívá v to· Že se racsaický oxebicyklo £з»Э»о] oktanon-acylát obecného vzorce (♦)·!!R | a hydrogen atom is an alkyl group of 1 to 7 carbon atoms or a phenyl group. This process consists in the formation of a racsaic oxebicyclo [zinc] octanone acylate of the general formula (♦).
ve které·in which·
R| aá shora uvedený význe·, podrobí enzymaticky etereospecifické hydrolýze acylátu. načež ее sloučenina obecného vzorce (-)-!» ve kterém R znamená skupinu vzorceR | as described above, it undergoes enzymatically ether-specific hydrolysis of the acylate. whereupon a compound of formula (-) - wherein R is a group of formula
CS 268*41 B2CS 268 * 41 B2
kde né shora uvedený význa·. oddělí od znýdelněné sloučeniny obecného vzorce (+)-I. v· které· R znaaená atoa vodíku, nebo a· znýdelněné sloučenina obecného vzorce (-)-!» ve které· R znanená sto· vodíku, oddělí od neznýdelnšné sloučeniny vzorce (+)-11.wherein the aforementioned meaning is not. separated from the saponified compound of formula (+) - I. wherein R denotes atoa hydrogen, or a sub-saponified compound of formula (-) - in which R denotes one hundred hydrogen, separates from the non-saponifiable compound of formula (+) - 11.
□estliže R^ znaaená alkylovou skupinu · 1 až 7 atoey uhlíku, pak jsou tekovýni skupinani ainěny «ethylové skupina, ethylová skupina, n-propylově skupina, isopropylové skupina, n-butylová skupina, isobutylová skupina, sek.butylové skupina, terc.butylové skupina, n-pentylové skupina, isopsntylová skupina, eek.pentylová skupina, neopentylová skupina. n«hsxylová skupina, isohexylová skupina, n-heptylová skupina, ieoheptylové skupina atd.If R is an alkyl group of 1 to 7 carbon atoms, then the ethyl group is ethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. a group, an n-pentyl group, an isopentyl group, an e-pentyl group, a neopentyl group. n-hexyl, isohexyl, n-heptyl, ioheptyl, etc.
Sloučenina obecného vzorce (-)-l jsou cennýni Meziprodukty při syntéze fsrsekologicky cenných analogů prostsglsndinu · proetscyklinu (srov. například O.Blndra, R.Bindra. Frostaglandin Synthseis. Acadenic Prese. New York 1977 a C. Szantay. L.Novak. Synthesis of Prostaglandins. Akadesiai Kládo. Budapešť. 1978).Compounds of formula (-) - 1 are valuable Intermediates in the synthesis of physiologically valuable analogs of prostsgginine · proetscycline (cf., for example, O. Lindra, R. Bindra. Frostaglandin Synthseis. Acadenic Prese. New York 1977 and C. Szantay. L. Novak. Synthesis of Prostaglandins, Akadesiai Kládo, Budapest, 1978).
К syntéze eloučenin.které jsou analogické jako přlrodný produkty, je zapotřebí esterů této řady enantioaerů,For the synthesis of compounds which are analogous to the natural products, esters of this series of enantiomers are required,
I když jsou znány ayntézy asymetrických sloučenin, je při technické výrobě výhodné zavádění optické aktivity cestou dělaní ráčenétu и Meziproduktu déle uvedeného vzore* (+)-3. Přitom jsou zapotřebí následující reakční etupnši 1* Znýdslnění lektonu na hydroxykyeelinu.Although the asynthesis of asymmetric compounds is known, it is advantageous in the technical manufacture of introducing optical activity via the ratcheting of the intermediate of the aforementioned formula (+) - 3. In this case, the following reaction steps are required to influence the lecton on the hydroxyalkyleeline.
2, Převedení na enše diastereoaernlch solí, například poaocí d- -fenylethylaainu.2, Conversion to an enantiomer of diastereoaernal salts, for example using d-phenylethylaine.
3, Krystalizscs za účele· získání diastereomerní čisté soli.3, Crystallizscs in order to obtain diastereomeric pure salt.
4, Převedení soli na opticky aktivní lakton vzorce (-)-3.4, Conversion of the salt to an optically active lactone of formula (-) - 3.
5, Další reakce za vzniku opticky aktivního Meziproduktu obecného vzorce (-)-I.5, Further Reaction to Form an Optically Active Intermediate of Formula (-) - I.
V důsledku tendence hydroxykyeeliny znovu zpětně tvořit lakton. dříve než by bylo nožné provést vyčištěni optickou cestou, jakož i v důsledku ztrát na výtěžku při kryetalizaci. se déle uvedený postup neosvědčil.Due to the tendency of the hydroxyalkyleelines to re-form the lactone. before it would be possible to purify by optical means, as well as due to loss of yield in crystallization. the aforementioned procedure did not work.
HOHIM
CCOHCCOH
dělení racemáturacemate separation
---> někojik stupňů---> some degrees
[(-)-1][(-) - 2]
Při postupu podle předloženého vynálezu es děleni provádí ne stupni racemlckých 7<*-acyloxy-6Д•hydroxymsthyl-2*oxsbicyklo [3»3»oJ aktan-3-onů vzorce enzymatický· zmýdelněním» které vede ke směsi produktů· ze které se eohou žádané sloučeniny vzorce (-)-X zieket buď extrakci nebo z vodné fáze·In the process of the present invention, the separation is carried out at the racemic step of the enzymatic saponification of the acyloxy-6β-hydroxymethyl-2 * oxsbicyclo [3.3.1.0] actan-3-ones of the formula resulting in a mixture of products from which the desired compounds of formula (-) - X can either be extracted or from the aqueous phase ·
Výchozí látky ee dají vyrábět postupem podle britského patentového spisu č· 1 579 464, Použití opticky sktivních esterů obecného vzorce (-)-I· ve kteréa R znamená skupinu vzorceThe starting materials can be prepared according to the process described in British Patent Specification No. 1,579,464. The use of optically selective esters of the formula (-) - I in which R represents a group of
získaných postupem podle vynálezu» jako meziproduktů pro výrobu farsakologicky cenných analogů prostaglandlnu a prostacyklinu» vyplývá již ze ahora citovaných publikací·obtained by the process according to the invention »as intermediates for the production of pharmacologically valuable analogues of prostaglandin and prostacyclin» follows from the references cited above.
Rovněž získaný opticky aktivní diol obecného vzorce (-)-I» ve kteréa R znamená atom vodíku» lze používat zvláště tehdy» když ee při následující syntéze auei nejdříve chránit primární hydroxylové skupina a sekundární hydroxylové skupina sůže zůstat volná· Tak jo tonu například v případě syntézy aeziproduktů karbacyklinu» jak se popisuje v evropské· patentovém spisu EP 41 661· □ako enzymy se pro postup podls vynálezu hodí výhodně •Subtiliain* z Bscillus subtilis (výrobek firmy Boehrlngsr» Mannheim)The optically active diol of the formula (-) - I also obtained in which R represents a hydrogen atom can also be used, in particular, when the primary hydroxyl group is first protected in a subsequent synthesis and the secondary hydroxyl group can remain free. Synthesis of carbacycline-ai-products as described in EP 41 661 as enzymes are preferably used as enzymes for the process according to the invention. Subtiliain * from Bscillus subtilis (manufactured by Boehrlngsr Mannheim)
Lipáza Sclerotlnia* (výrobek firmy Nagase)Lipase Sclerotlnia * (manufactured by Nagase)
Alksline Proteinase (výrobek firmy Nagase) proteáza z Bacillus subtilis *Alcslsee T* (výrobek firmy NOVO)Alksline Proteinase (manufactured by Nagase) protease from Bacillus subtilis * Alcslsee T * (manufactured by NOVO)
Tyto enzymy se mohou používat jak v rozpuštěném» suspendovaném tak i iaobilizovanéa stavu (například ve formě eephsrosy aktivované bromkyanem (BrCN) nebo na oxlranakrylových perličkách nebo v nějaké jiné imobillzovené formě)These enzymes can be used in both the suspended and immobilized state (e.g., in the form of cyanogen bromide-activated eephsrosy (BrCN) or on oxlacrylic beads or in some other immobilized form)
Opticky aktivní deriváty oxabicyklooktanolonu obecného vzorce (-)-I» které lze připravit postupe· podls vynálezu» jsou cennými meziprodukty peo syntéze farmakologlcky účinných prosteglsndinů a prostacyklinů· Ukázalo se» že větěi Část stereospecifleky hydrolyzujících enzymů zmýdelní racemické sloučeniny obecného vzorce (+)-11 na opticky aktivní diol obecného vzorce (♦)-!» ve kterém R znamená atom vodíku» přičeši složka použitého racemátu vzorce (+)-II» odpovídající ve své absolutní konfiguraci přirozenéau prostacyklinů PGO^» zůstane nexmýdelnénaThe optically active oxabicyclooctanolone derivatives of formula (-) - »which can be prepared by the process of the invention are valuable intermediates for the synthesis of pharmacologically active prosteglsndins and prostacyclins. to the optically active diol of the general formula (♦) - »in which R represents a hydrogen atom» the racemate component of the formula (+) - II used corresponding to its absolute configuration of the natural prostacyclins PGO?
CS 26SS41 B2CS 26SS41 B2
a po odděleni diolu ae může použit к syntéza analogů prostecyklinu a přirozenou konfiguraci.and after separation of the diol and e may be used to synthesize prostecycline analogs and natural configuration.
Jiné enzymy opět zmýdelňují z obou aložek použitého racamétu obecného vzorce (♦ )-II formu a přirozenou konfiguraci na diol obecného vzorce (-)-I, ve kterém R znamená atoa vodiku, zatím co *neeprévný enantiomar a konfiguraci, které neodpovídá přirozené konfiguraci, zůetává nezmýdelněn, V toato případě ee diol využívá к eyntéze proetacyklinů, které jmou analogy PGD?·Other enzymes re-saponify from both components of the used racamate of formula (♦) -II the form and natural configuration to the diol of formula (-) - I in which R is atoa hydrogen, while * an opaque enantiomar and a configuration that does not match the it remains unsaponified, in this case ee diol uses proetacyclines to synthesize PGD analogues? ·
Poetup podle vynálezu ee jinak provádí za podmínek, které jeou o sobě známé, a které jaou znéaé pro enzymatické reakce, Průběh enzymatické přeměny ee sleduje analýzou průběžně odebíraných vzorků, Jako analytické metody jaou vhodné vysoce účinná kapalinové chromatografie nebo rychlé analýzy chromatografií na tenké vrstvě (siliksgsl vyráběný firmou Herek, Darmstadt· vyvíjeni pomocí směsi methylenchloridu a acetonu v poměru 1:1 a detekce (zbarvení) pomocí kyeeliny sírové).The process according to the invention is otherwise carried out under conditions known per se which are known for enzymatic reactions. The course of the enzymatic conversion is monitored by analysis of continuously sampled samples. High performance liquid chromatography or rapid analysis by thin layer chromatography (analytical methods) are suitable. siliksgsl manufactured by Herek, Darmstadt · developed with a 1: 1 mixture of methylene chloride and acetone and detection (coloring) with sulfuric cyeeline).
Když zreaguje 50 % z použitého racamického substrátu, reakce se přeruší a reakční směs ss zpracuje.When 50% of the racemic substrate used is reacted, the reaction is stopped and the reaction mixture is worked up.
Postup podle vynálezu je vhodný zejména ke atereoepecifickému zmýdelňování následujících mezistupňů proetaglendinutThe process according to the invention is particularly suitable for athereoepecific saponification of the following intermediate stages of proetaglendinut
OO
i b - coi b - what
Následující příklady slouží к bližěíau objasnění postupu podle vynálezu. Tyto příklady však rozaah vynálezu v žádná® aaěru neoaezujl.The following examples serve to illustrate the process of the invention. However, these examples did not limit the scope of the invention to any extent.
Přiklad 1Example 1
300 ag (♦) -7<X -benzoyloxy-6 fy -hydroxyaethyl-2-oxabicyklo f3,3,oj oktsn-3-onu se rozpustí v 9 ·1 ethanolu а к ziakanáau roztoku ae přidá 750 ag Alkaline Proteinese* (výrobek firay Nagaae) ve 100 ·1 O,1M roztoku fosfátového pufru o pH 7. Reakčni roztok se protřepává při teplotě 2· °C na rotační třepačce# přlčeaž ae průběh reakce aleduje analýzou průběžně odebíraných vzorků# Po 19 hodinách reakčni doby je 50 % použitého substrátu přeaěněno# Získaná aaěa ae nyní třikrát extrahuje vždy 50 al aethylieobutylketonu, přičeaž nezreagovaný benzoát přechází do ·βthylieobutylketonové fáze, zatíaco zaýdelněná sloučenina zůstává ve vodná fázi#300 g of (7) -7-N-benzoyloxy-6-hydroxy-2-oxabicyclo [3.3.0] oct-3-one is dissolved in 9 · 1 ethanol and the solution is added and 750 g of Alkaline Proteinese * (product) is added. firay Nagaae) in 100 · 1.0 0.1M phosphate buffer solution at pH 7. Shake the reaction solution at 2 ° C on a rotary shaker # until the reaction is followed by analyzing the sampled # # After 19 hours reaction time, 50% of the used The obtained aaa and ae now extracts three times with 50 [mu] l of ethyl ethyl isobutyl ketone each while unreacted benzoate is transferred to the β-ethyl isobutyl ketone phase, while the saponified compound remains in the aqueous phase #
Methylisobutylketonová extrakty ae spoji a zahusti ae za anížsnáho tlaku к suchu. Zbylý odparek ae překryttaluje z acetonu* Zieká se 135 ag (-)-7cK -benzoyloxy-6/ý-hydroхужеthyl-2-oxabicyкlo £3,3,0^ -oktan*3-onu o teplotě táni 116 až 117 °C a a optickou otáčivostí - -80,5 0 (c 1,050 v chloroformu)·The methyl isobutyl ketone extracts are combined and concentrated to dryness at an extreme pressure. The residual residue was recrystallized from acetone. 135 g of (-) - 7C-benzoyloxy-6H-hydrohydro-2-oxabicyclo [3.3.0] octane-3-one having a melting point of 116 DEG-117 DEG C. were obtained. optical rotation - -80.5 0 (c 1.050 in chloroform) ·
Příklad 2Example 2
300 ag (♦)-7o<-benzoyloxy-6^-hydroxyaathyl-2-oxebicyklo [3,39oj oktan-3-onu se suspenduje ve 100 «1 0,1 И roztoku fosfátového pufru o PH 7, к získaná suspenzi ae přidá 750 ag Subsilisinu z Bacillus subtilis (výrobek fiřey Boehringsr, Mannhei·) a aaěa ae hoeogenizujs rychloběžný· aíchadle· (Ultra-Turrax)· Suspenze se potoa protřepává po dobu 16 hodin při teplotě 28 °C na rotační třepačce · po této době je 50 % z použitého racaického substrátu zaýdsiněno. Saěs se nyní zahustí к euchu za vakua vodní vývěvy, zbytek se třikrát vyaývá aathanolea. spojená aethanolová eluáty se znovu odpaří к suchu a odparek se chroaatografиje přes silikagel (za použiti saěai methylenchloridu a acetonu v poaěru 66:33 jako slučnlho Činidla)# Nejdříve eluovaná frakce 1 obsahuje 122 ag (-)-7^ -benzoyloxy-6/5-hydroxyaethyl-2-oxabicyklo £3,3,oJ oktan-3-onu o teplotě tání 114 až 116 °C a optická o táčivoati Q -82,3 0 (c · 1,015 v aethanolu).300 g (♦) -7o <benzoyloxy-6-2--hydroxyaathyl oxebicyklo [3,3 9 octan-3-one are suspended in 100 «1 И 0.1 phosphate buffer pH 7, the resulting suspension к and add 750 g of Subsilisin from Bacillus subtilis (manufactured by Boehringsr, Mannhei) and ae eeogenize with high speed agitator (Ultra-Turrax). The suspension is shaken for 16 hours at 28 ° C on a rotary shaker. 50% of the racaic substrate used is contaminated. Saesa is now concentrated to a vacuum under a water pump vacuum, the remainder is extracted three times with aathanolea. the combined ethanolic eluates were re-evaporated to dryness and the residue chromatographed over silica gel (using methylene chloride and acetone in 66:33 as a reagent) # The eluting first fraction 1 contained 122 g of (-) - 7'-benzoyloxy-6/5 -hydroxyaethyl-2-oxabicyclo £ 3.3 octan-3-one, mp 114-116 ° C, the optical táčivoati Q 0 -82.3 (c 1.015 in methanol, to ·).
Přiklad 3Example 3
Za podaínek popsaných v přikladu 2 se na 300 ag (+)·7<Χ -benzoyloxy-6,J -hydroxyaethyl-2-oxabicyklo ^3,3,Oj7 oktan-3-onu ve fosfátová· pufru o pH 7 působí 750 ag lipázy Sclerotine (výrobek firay Nagase) po dobu 64 hodin při teplotě 28 °C# Po odděleni zaýdslněného anantioaeru s nepřirozenou konfigurací poaocí sloupcové chroaatografie se zieká 115 ag (•)-7P< benzoyloxy-6/3-hydroxyaethyl-2-oxabicyklo /Ъ,3,oj oktan-3-onu o teplotě tání 115 až 116 °C a optické otáčivoati^J D -79,· ° (c - 1,02 v aethanolu).Under the conditions described in Example 2, 300 g of (+) - 7 ' -benzoyloxy-6,11-hydroxy-ethyl-2-oxabicyclo [3.3.0] octan-3-one in phosphate buffer at pH 7 is treated with 750 g. Sclerotine lipase (manufactured by firay Nagase) for 64 hours at 28 ° C # 115 g of (•) -7P <benzoyloxy-6/3-hydroxyaethyl-2-oxabicyclo / Ъ are recovered after separation of the saturated anantioamer with unnatural configuration by column chromatography. 115 DEG-116 DEG C. and an optical rotation of [.alpha.] D -79.0 DEG (c = 1.02 in ethanol).
Příklad 4Example 4
Za podaínek popaaných v příkladu 2 se hydrolyzuje 300 ag (♦)-7č<-benzoyloxy-6/J -hydroxyaethyl-2-oxabicyklo £з,3,о/ oktan-3-onu ve fosfátová· pufru o pH 7 půeobenía 750 ag Alcalasy T (výrobek firay NOVO) po dobu 40 hodin při teplotě 28 °C. Po rozdělení reakčni aaěai sloupcovou chroaetografií ae získá 142 ag (-)-7o< -benzoyloxy-6/5 -hydroxyaethyl-2-oxabicyklo ^3,3,oj oktan-3-onu o teplotě táni 112 až 114 °C a optické otáčivoati£o/J D - -77,1 0 (c 1,005 v aethanolu).Under the conditions described in Example 2, 300 g of (R) -7 N -benzoyloxy-6 H -hydroxyethyl-2-oxabicyclo [3.3.0] octan-3-one is hydrolyzed in phosphate buffer at pH 7 of action and 750 g. Alcalases T (firay NOVO product) for 40 hours at 28 ° C. After separation by reaction and column chromatography, 142 g of (-) - 7O-benzoyloxy-6,5-hydroxy-ethyl-2-oxabicyclo [3.3.1] octan-3-one having a melting point of 112 DEG-114 DEG C. and optical rotation is obtained. [Α] D - -77.0 ° (c 1.005 in ethanol).
Příklad 5Example 5
Za podaínek popsaných v příkladu 2 ea na 300 ag (*)-7Л-benzoyl-oxy-6/4-hydroxyaathyl-2-oxabicyklo £з,3,о] oktan-3-onu va fosfátové· pufru o PH 7 působí 750 ag proteázy z Bacillus aubtilia po dobu 15 hodin při teplotě 28 °C# Po rozdělení reakčni eaěai sloupcovou chroaetografií sa získá 119 ag t-)-7af-benzoyloxy-6/3 -hydroxyaethyl-2-oxablcyklo £з.3,OJ oktan-3-onu o teplotě tání 113 až 115 °C a optické otáčivoeti Q -78,9 0 (c · 1,025 v aethanolu)·Under the conditions described in Example 2 and 300 g of (*) - 7-L-benzoyloxy-6/4-hydroxy-ethyl-2-oxabicyclo [2,3-b] octan-3-one in a phosphate buffer of pH 7 acts 750 ag of protease from Bacillus aubtilia for 15 hours at 28 ° C. After separation by reaction and column chromatography, 119 ag of 1- (7-benzoyloxy-6/3-hydroxy-ethyl-2-oxabicyclo-3-ol, octane-3) was obtained. -one, m.p. 113-115 ° C and optical otáčivoeti Q 0 -78.9 (c 1.025 in methanol, to ·) ·
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863638762 DE3638762A1 (en) | 1986-11-13 | 1986-11-13 | RACEMAT CLEAVAGE OF 7 (ALPHA) -ACYLOXY-6SS-HYDROXY-METHYL-2-OXABICYCLO (3.3.0) OCTAN-3-ONES BY STEREO-SPECIFIC ENZYMATIC ACYLATE HYDROLYSIS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS815087A2 CS815087A2 (en) | 1989-08-14 |
| CS268841B2 true CS268841B2 (en) | 1990-04-11 |
Family
ID=6313862
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS878150A CS268841B2 (en) | 1986-11-13 | 1987-11-13 | Method of optically active(-)-oxabicyclo/3,3,0/octanoles production |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0271433B1 (en) |
| JP (1) | JPH01501360A (en) |
| AT (1) | ATE85084T1 (en) |
| BG (1) | BG48098A3 (en) |
| CS (1) | CS268841B2 (en) |
| DD (1) | DD279689A5 (en) |
| DE (2) | DE3638762A1 (en) |
| ES (1) | ES2053577T3 (en) |
| GR (1) | GR3007127T3 (en) |
| HU (1) | HU202289B (en) |
| WO (1) | WO1988003570A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9108376D0 (en) * | 1991-04-19 | 1991-06-05 | Enzymatix Ltd | Cyclopentenes |
| AU3961493A (en) * | 1992-04-21 | 1993-11-18 | Chiroscience Limited | Chiral cyclopentene derivatives and their preparation |
| US5840923A (en) * | 1992-04-21 | 1998-11-24 | Chiroscience Limited | Chiral cyclopentene derivatives and their preparation |
| US5215918A (en) * | 1992-06-19 | 1993-06-01 | Bend Research, Inc. | Enantiomeric enrichment of (R,S)-3-quinuclidinol |
| DE4435242A1 (en) * | 1994-10-04 | 1996-04-11 | Hoechst Ag | Process for the enzymatic separation of enantiomers of rac-2-oxotricyclo 2,2,1,0 · 3 ·, · 5 · -heptan-7-carboxylic acid or the -carboxylic acid ester |
| ES2274854T3 (en) | 2000-05-08 | 2007-06-01 | Pfizer Products Inc. | ENZYMATIC RESOLUTION OF SELECTIVE MODULATORS OF THE STROGEN RECEIVER. |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SE431750B (en) * | 1977-05-26 | 1984-02-27 | Chinoin Gyogyszer Es Vegyeszet | PROCEDURE FOR THE PREPARATION OF BICYCLIC LACTON DIODE DERIVATIVES |
| DE3021895A1 (en) * | 1980-06-06 | 1981-12-24 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | NEW METHOD FOR PRODUCING CARBACYCLIN INTERMEDIATE PRODUCTS |
| EP0127386B1 (en) * | 1983-05-25 | 1987-08-05 | Sumitomo Chemical Company, Limited | Process for producing optically active cyclopentenolones |
| JPS61280294A (en) * | 1985-06-04 | 1986-12-10 | Nisshin Flour Milling Co Ltd | Optically active carbacycline intermediate and production thereof |
-
1986
- 1986-11-13 DE DE19863638762 patent/DE3638762A1/en not_active Withdrawn
-
1987
- 1987-11-11 DD DD87308937A patent/DD279689A5/en not_active IP Right Cessation
- 1987-11-12 ES ES87730148T patent/ES2053577T3/en not_active Expired - Lifetime
- 1987-11-12 WO PCT/DE1987/000520 patent/WO1988003570A1/en unknown
- 1987-11-12 JP JP62506741A patent/JPH01501360A/en active Pending
- 1987-11-12 HU HU875796A patent/HU202289B/en not_active IP Right Cessation
- 1987-11-12 AT AT87730148T patent/ATE85084T1/en not_active IP Right Cessation
- 1987-11-12 DE DE8787730148T patent/DE3783885D1/en not_active Expired - Lifetime
- 1987-11-12 EP EP87730148A patent/EP0271433B1/en not_active Expired - Lifetime
- 1987-11-13 CS CS878150A patent/CS268841B2/en unknown
-
1988
- 1988-07-12 BG BG084850A patent/BG48098A3/en unknown
-
1993
- 1993-02-23 GR GR930400363T patent/GR3007127T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU202289B (en) | 1991-02-28 |
| CS815087A2 (en) | 1989-08-14 |
| EP0271433B1 (en) | 1993-01-27 |
| EP0271433A1 (en) | 1988-06-15 |
| DE3783885D1 (en) | 1993-03-11 |
| DD279689A5 (en) | 1990-06-13 |
| ATE85084T1 (en) | 1993-02-15 |
| GR3007127T3 (en) | 1993-07-30 |
| BG48098A3 (en) | 1990-11-15 |
| HUT47155A (en) | 1989-01-30 |
| WO1988003570A1 (en) | 1988-05-19 |
| DE3638762A1 (en) | 1988-05-26 |
| ES2053577T3 (en) | 1994-08-01 |
| JPH01501360A (en) | 1989-05-18 |
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