NO165024B - L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5 - THIADIAZOLE. - Google Patents
L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5 - THIADIAZOLE. Download PDFInfo
- Publication number
- NO165024B NO165024B NO870919A NO870919A NO165024B NO 165024 B NO165024 B NO 165024B NO 870919 A NO870919 A NO 870919A NO 870919 A NO870919 A NO 870919A NO 165024 B NO165024 B NO 165024B
- Authority
- NO
- Norway
- Prior art keywords
- thiadiazole
- morpholino
- tert
- timolol
- hydroxypropoxy
- Prior art date
Links
- 239000002253 acid Substances 0.000 title description 7
- BLJRIMJGRPQVNF-UHFFFAOYSA-N timolol Chemical compound CC(C)(C)NCC(O)COC1=NSN=C1N1CCOCC1 BLJRIMJGRPQVNF-UHFFFAOYSA-N 0.000 title 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229960004605 timolol Drugs 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000006467 substitution reaction Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- DWUZILHYAJBUBR-UHFFFAOYSA-N 4-morpholin-4-yl-1,2,5-thiadiazol-3-one Chemical compound OC1=NSN=C1N1CCOCC1 DWUZILHYAJBUBR-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SULAQIPCRIBAKU-UHFFFAOYSA-N 1-tert-butylazetidin-3-ol;hydrochloride Chemical compound Cl.CC(C)(C)N1CC(O)C1 SULAQIPCRIBAKU-UHFFFAOYSA-N 0.000 description 3
- GFADKTZJVHXFGR-UHFFFAOYSA-N 4-(4-propan-2-yloxy-1,2,5-thiadiazol-3-yl)morpholine Chemical compound CC(C)OC1=NSN=C1N1CCOCC1 GFADKTZJVHXFGR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000003301 hydrolyzing effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- KGCYYMUHGZTDQN-YUMQZZPRSA-N (3S,4S)-3,4-diacetyl-3,4-dihydroxyoxolane-2,5-dione Chemical compound C(C)(=O)[C@]1([C@](C(=O)OC1=O)(O)C(C)=O)O KGCYYMUHGZTDQN-YUMQZZPRSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960001270 d- tartaric acid Drugs 0.000 description 2
- -1 diacetyl ester Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- MUHCEAIVGKVBHE-UHFFFAOYSA-N 1,2,5-thiadiazol-3-one Chemical class OC=1C=NSN=1 MUHCEAIVGKVBHE-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical class C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZQQSYPZAPHRXRY-UHFFFAOYSA-N 1-hydroxyazetidine Chemical compound ON1CCC1 ZQQSYPZAPHRXRY-UHFFFAOYSA-N 0.000 description 1
- SSQMTFZAUDZFTK-UHFFFAOYSA-N 1-tert-butylazetidin-3-ol Chemical compound CC(C)(C)N1CC(O)C1 SSQMTFZAUDZFTK-UHFFFAOYSA-N 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- AWWWAQNWEDIJBN-UHFFFAOYSA-N 3-chloro-4-propan-2-yloxy-1,2,5-thiadiazole Chemical compound CC(C)OC1=NSN=C1Cl AWWWAQNWEDIJBN-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 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
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører L-vinsyre-O-monoestere av R,S-3-morfolino-4-(3<1->tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol, og det særegne ved forbindelsene er at de har den generelle formel: The present invention relates to L-tartaric O-monoesters of R,S-3-morpholino-4-(3<1->tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole, and the peculiarity of the compounds is that they have the general formula:
hvor R4 og R5 er like og er rettkjedede alkanoylgrupper som inneholder 1-5 karbonatomer i alkyldelen eller benzoylgrup-per. where R4 and R5 are the same and are straight-chain alkanoyl groups containing 1-5 carbon atoms in the alkyl part or benzoyl groups.
Den ovennevnte L-vinsyre-O-monoester av R,S-3-morfolino-4-(3'-tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol kan fordelaktig fremstilles ved at R,S-3-morfolino-4-(3<1->tert-butylamino-2 '-hydroksypropoksy)-1,2,5-tiadiazol med formel: i et inert, vannfritt organisk oppløsningsmiddel og ved en temperatur fra 0 til 70°C, omsettes med et dialkanoyl- eller dibenzoyl-L-vinsyreanhydrid med formel: The above-mentioned L-tartaric O-monoester of R,S-3-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole can advantageously be prepared by R,S- 3-morpholino-4-(3<1->tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole of the formula: in an inert, anhydrous organic solvent and at a temperature from 0 to 70°C, is reacted with a dialkanoyl or dibenzoyl-L-tartaric anhydride of formula:
hvor R4 og R5 har den ovennevnte betydning. where R4 and R5 have the above meaning.
De nevnte L-vinsyre-O-monoestere av R,S-3-morfolino-4-(3'-tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol er nye forbindelser og er særlig fordelaktige som utgangsmaterial for fremstilling av den terapeutisk aktive forbindelse (p-blokkerende middel) S-timolol ved at de nevnte estere oppløses ved utkrystallisasjon fra en C1-C5 alkohol eller fra en vandig alkohol av en slik alkohol, ved pH fra 7 til 2 og temperatur fra 0 til 30°C, for erholdelse av S-forbindelsen i krystallisert form, og denne S-forbindelse underkastes en syrehydrolyse i en vandig oppløsning slik at den ønskede S-timololbase dannes. Denne prosess er omhandlet i norsk utlegn.skrift 158.020, og gir et svært godt utbytte både kjemisk og optisk. The aforementioned L-tartaric O-monoesters of R,S-3-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole are new compounds and are particularly advantageous as starting material for the preparation of the therapeutically active compound (β-blocking agent) S-timolol by dissolving the said esters by crystallization from a C1-C5 alcohol or from an aqueous alcohol of such an alcohol, at pH from 7 to 2 and temperature from 0 to 30°C, to obtain the S-compound in crystallized form, and this S-compound is subjected to an acid hydrolysis in an aqueous solution so that the desired S-timolol base is formed. This process is described in Norwegian publication document 158.020, and gives a very good yield both chemically and optically.
De nye monoestere kan fremstilles på den ovennevnte måte i et inert, vannfritt organisk oppløsningsmiddel ved temperatur 0 til 70°C ved omsetningen mellom det angitte R,S-3-morfolino-4-(3<1->tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol og det angitte dialkanoyl- eller dibenzoyl-L-vinsyreanhydrid, hvor da substitusjonen under de angitte betingelser bare foregår som en o-substitusjon (dvs. uten dannelse av N-substituerte molekyler, bekreftet ved hjelp av massespektra av produktene). Hvis produktet hadde vært N-substituert, dvs. et amid, ville det ikke hydrolysere i noen vesentlig grad under hydrolyserende betingelser, til forskjell fra et O-substituert produkt, dvs. en ester. Ved denne fremgangsmåte skjer det selektivt en O-esterdannelse som muliggjør en dannelse av indre hydrogenbindinger ved nitrogenatomene, noe som er en forutsetning for en vellykket selektiv oppløsning ved fremstillingen av S-timolol som angitt i det nevnte norske utlegningsskrift 158.020. I det nevnte uti.skrift er fremskrittet overfor en rekke tidligere foreslåtte prosesser for fremstilling av S-timolol angitt mer detaljert og medtas ikke her. The new monoesters can be prepared in the above-mentioned manner in an inert, anhydrous organic solvent at a temperature of 0 to 70°C by the reaction between the indicated R,S-3-morpholino-4-(3<1->tert-butylamino-2' -hydroxypropoxy)-1,2,5-thiadiazole and the specified dialkanoyl or dibenzoyl-L-tartaric anhydride, where the substitution under the specified conditions only takes place as an o-substitution (i.e. without formation of N-substituted molecules, confirmed by using mass spectra of the products). If the product had been N-substituted, i.e. an amide, it would not hydrolyse to any significant extent under hydrolysing conditions, unlike an O-substituted product, i.e. an ester. In this method, an O-ester formation occurs selectively which enables the formation of internal hydrogen bonds at the nitrogen atoms, which is a prerequisite for a successful selective resolution in the production of S-timolol as indicated in the aforementioned Norwegian explanatory document 158.020. In the above-mentioned publication, the progress towards a number of previously proposed processes for the production of S-timolol is stated in more detail and is not included here.
I det følgende er hele grunnlaget for oppfinnelsen anført, først den selektive substitusjon og konfigurasjon for forbindelsen i henhold til oppfinnelsen (utgangsforbindelse/- mellomprodukt) og dens fremstilling, og dernest grunnlaget for en videre syntese til ferdigproduktet S-timolol. Ved fremstillingen av utgangsforbindelsen skjer substitusjonen under de angitte betingelser bare som en O-substitusjon, noe som også bekreftes av oppnådde massespektra av produktene, spektra som ikke inneholder fragmenter som er karakteristiske for N-substituerte molekyler, mens fragmentet m/z 86 (CH = NH-C(CH3)3, altså morfolinogruppen) er sterkt. Dersom produktet var N-substituert, dvs. et amid, ville det ikke gjennomgå hydrolyse i noen vesentlig grad under hydrolyserende betingelser som er karakteristiske for et O-substituert produkt, dvs. en ester. In the following, the entire basis for the invention is stated, first the selective substitution and configuration for the compound according to the invention (starting compound/intermediate) and its preparation, and then the basis for a further synthesis to the finished product S-timolol. In the preparation of the starting compound, the substitution occurs under the stated conditions only as an O-substitution, which is also confirmed by the obtained mass spectra of the products, spectra which do not contain fragments characteristic of N-substituted molecules, while the fragment m/z 86 (CH = NH-C(CH3)3, i.e. the morpholino group) is strong. If the product were N-substituted, i.e. an amide, it would not undergo hydrolysis to any significant extent under hydrolyzing conditions characteristic of an O-substituted product, i.e. an ester.
Det ble videre svært overraskende funnet at angjeldende R,S-timolol-dialkanoyl- og dibenzoyl-L-vinsyre-O-monoestere kunne oppløses med et svært godt utbytte både kjemisk og optisk ved å krystallisere det ovennevnte racemat fra C^-C5-alkoholer slik som metanol, etanol, N-propanol eller isopropanol, eller fra deres blandinger eller fra vandige oppløsninger derav i et pH-område fra 7 til 2 og i et temperaturområde fra 0 til 30°C hvorved S-enantiomeren av de tilsvarende timolol-dialkanoyl- og dibenzoyl-L-vinsyre-O-monoestere (formel S-I-L), som er den minst oppløselige forbindelse i oppløs-ningsmidlene eller oppløsningsmiddelblandingene, utkrystal-liseres og kan separeres fra moderlutene ved hjelp av kjente midler. It was further very surprisingly found that the relevant R,S-timolol dialkanoyl and dibenzoyl-L-tartaric acid O-monoesters could be resolved with a very good yield both chemically and optically by crystallizing the above-mentioned racemate from C^-C5 alcohols such as methanol, ethanol, N-propanol or isopropanol, or from their mixtures or from aqueous solutions thereof in a pH range from 7 to 2 and in a temperature range from 0 to 30°C whereby the S-enantiomer of the corresponding timolol dialkanoyl - and dibenzoyl-L-tartaric acid-O-monoesters (formula S-I-L), which is the least soluble compound in the solvents or solvent mixtures, crystallizes out and can be separated from the mother liquors using known means.
Hele det ovennevnte kompleks av reaksjoner fremgår skjematisk av følgende reaksjonsskjerna, hvor den første del illustrerer utgangsmonoesteren (gjenstanden for den foreliggende oppfinnelse) og dens fremstilling, og/den siste del viser den videre forarbeidelse av denne monoester til terapeutisk aktiv S-timolol (gjenstanden for det tidligere nevnte NO utlegn.-skrift 158.020) og er medtatt i det vesentlige for å lette oversikten. The entire above-mentioned complex of reactions appears schematically from the following reaction core, where the first part illustrates the starting monoester (the object of the present invention) and its preparation, and/the last part shows the further processing of this monoester into therapeutically active S-timolol (the object of the previously mentioned NO ulegn.-skrift 158.020) and is included essentially to facilitate the overview.
Det nedennevnte fordelaktige optiske utbytte skyldes sannsyn-ligvis primært den store affinitet til S-formen av timolol-L-vinsyrederivatet, på grunn av dets stereokjemiske struktur, under de anvendte krystallisasjonsbetingelser, til å danne et indre salt, og den lave oppløselighet av dette salt i oppløsningsmidlet som brukes til krystallisasjonen ved oppløsningen av racematet. The below-mentioned advantageous optical yield is probably due primarily to the great affinity of the S-form of the timolol-L-tartaric acid derivative, due to its stereochemical structure, under the crystallization conditions used, to form an inner salt, and the low solubility of this salt in the solvent used for the crystallization by dissolving the racemate.
En indikasjon på at S-timolol-L-vinsyrederivatet er tilstede i form av et indre salt, er toppene som iakttas i IR-spektraene, som er karakteristiske for slike salter i området fra 1575 til 1600 cm-1 og 2250 til 2700 cm<-1>, (1 til 5 topper), og den iakttagelse som gjøres fra <13>C-NMR-spektra at signalet til karbonatom nr. 2 (jfr. strukturformelen i tabell 1 og verdiene i tabellen) har forflyttet seg 5 til 7 ppm mot det nedre område, noe som er karakteristisk for en syregruppe som danner en saltstruktur (-NH2-) (jfr. Acta. Chem. Scand. B 38 (1984) 67). Disse iakttagelser som er gjort på grunnlag av IR- og <l>^C-spektraene som underbygger tilstedeværelsen av en saltstruktur, indikerer også at reaksjonen mellom R,S-timolol og dialkanoyl- og dibenzoyl-L-vinsyreanhydridet finner sted som en O-substitusjon og ikke som en N-substitusjon, ettersom det i det sistnevnte tilfelle ikke ville finne sted noen dannelse av et indre salt. An indication that the S-timolol-L-tartaric acid derivative is present in the form of an inner salt is the peaks observed in the IR spectra, which are characteristic of such salts in the range from 1575 to 1600 cm-1 and 2250 to 2700 cm< -1>, (1 to 5 peaks), and the observation made from <13>C-NMR spectra that the signal of carbon atom no. 2 (cf. the structural formula in table 1 and the values in the table) has shifted 5 to 7 ppm towards the lower range, which is characteristic of an acid group forming a salt structure (-NH2-) (cf. Acta. Chem. Scand. B 38 (1984) 67). These observations made on the basis of the IR and <l>^C spectra supporting the presence of a salt structure also indicate that the reaction between R,S-timolol and the dialkanoyl and dibenzoyl-L-tartaric anhydrides takes place as an O- substitution and not as an N-substitution, since in the latter case no formation of an internal salt would take place.
Tabell 1 viser de kjemiske skift i <l>^C-NMR-spektraene for g-og R,S-timolol-diacetyl-L-vinsyre-O-monoestere og tilsvarende dibenzoylestere, samt for S-timolol-basen. S-timolol-basen kan frigjøres fra O-estrene ved syrehydrolyse i en vandig oppløsning i løpet av 1 til 24 timer i et pH-område fra 0 til 5 og i et temperaturområde fra 25 til 100°C ved å bruke f.eks. en mineralsyre slik som svovelsyre eller fosforsyre. Det har vist seg å være fordelaktig å koke ved tilbakeløps-temperatur i 10 timer med svovelsyre i en vandig oppløsning regulert til pH 2. Utvinningen av S-timolol-basen finner sted ved å ekstrahere den fra en reaksjonsblanding som er gjort alkalisk (pH 10 til 13) f.eks. med et alkalihydroksyd eller ammoniakk, over i et organisk oppløsningsmiddel som f.eks. metylenklorid, 1,2-dikloretan, benzen, toluen, etylacetat, etc, hvorfra S-timolol-basen utvinnes etter fradestillering av oppløsningsmidlet i et nesten kvantitativt utbytte og med en optisk renhet på mer enn 97 %. S-timolol-basen kan om ønsket renses ytterligere ved utkrystallisering fra et organisk oppløsningsmiddel, eller den kan overføres til det tilsvarende syreaddisjonssalt, slik som hydrokloridet eller hydrogenmaleatet, på en kjent måte. Table 1 shows the chemical shifts in the <1>C-NMR spectra for g- and R,S-timolol-diacetyl-L-tartaric acid-O-monoesters and corresponding dibenzoyl esters, as well as for the S-timolol base. The S-timolol base can be released from the O-esters by acid hydrolysis in an aqueous solution during 1 to 24 hours in a pH range from 0 to 5 and in a temperature range from 25 to 100°C using e.g. a mineral acid such as sulfuric or phosphoric acid. It has been found to be advantageous to boil at reflux temperature for 10 hours with sulfuric acid in an aqueous solution adjusted to pH 2. The recovery of the S-timolol base takes place by extracting it from a reaction mixture that has been made alkaline (pH 10 to 13) e.g. with an alkali hydroxide or ammonia, into an organic solvent such as e.g. methylene chloride, 1,2-dichloroethane, benzene, toluene, ethyl acetate, etc, from which the S-timolol base is recovered after distilling off the solvent in an almost quantitative yield and with an optical purity of more than 97%. If desired, the S-timolol base can be further purified by crystallization from an organic solvent, or it can be transferred to the corresponding acid addition salt, such as the hydrochloride or hydrogen maleate, in a known manner.
Oppløsningen av R,S-timolol ved å utkrystallisere den tilsvarende dialkanoyl- eller dibenzoyl-L-vinsyre-O-monoester, fortrinnsvis diacetylesteren, fra en alkohol eller en alkohol-vann-blanding ved en pH på <.! og i et temperaturområde fra 0 til 30°C hvorved S-timolol-L-vinsyre-O-monoesteren separeres i et godt utbytte og i optisk nesten ren form, og ved å hydrolysere denne i et pH-område fra 0 til 5 til S-timolol, har vist seg å være en særlig fordelaktig måte å fremstille forbindelsen på. The dissolution of R,S-timolol by crystallizing the corresponding dialkanoyl- or dibenzoyl-L-tartaric acid-O-monoester, preferably the diacetyl ester, from an alcohol or an alcohol-water mixture at a pH of <.! and in a temperature range from 0 to 30°C whereby the S-timolol-L-tartaric acid-O-monoester is separated in good yield and in optically almost pure form, and by hydrolyzing this in a pH range from 0 to 5 to S -timolol, has been shown to be a particularly advantageous way of preparing the compound.
I tillegg til de fremgangsmåter som er beskrevet i littera-turen, kan R,S-timolol også fremstilles ifølge en fremgangsmåte som er kjent og som er i overensstemmelse med det følgende reaksjonsskjema (jfr. f.eks. JP patenskrift nr. 7219259 eller ES patentskrift nr. 459725) ved å bruke utgangsmaterialet 3-hydroksy-4-morfolino-1,2,5-tiadiazol In addition to the methods described in the literature, R,S-timolol can also be prepared according to a method which is known and which is in accordance with the following reaction scheme (cf. e.g. JP patent no. 7219259 or ES patent document no. 459725) by using the starting material 3-hydroxy-4-morpholino-1,2,5-thiadiazole
eller, mer fordelaktig, et alkalimetallsalt derav (R5 = H, Na, K) og l-tert-butyl-3-azetidinol eller hydrokloridet derav eller et annet tilsvarende syreaddisjonssalt. Reaksionsskiema ( Eksempel på fremstilling av R. S- utaanasbase) or, more advantageously, an alkali metal salt thereof (R5 = H, Na, K) and 1-tert-butyl-3-azetidinol or its hydrochloride or another corresponding acid addition salt. Reaction scheme (Example of preparation of R. S- utaanase base)
Reaksjonen utføres fortrinnsvis i et inert organisk oppløs-ningsmiddel som f.eks. benzen, toluen, xylen, klorert alifatisk eller aromatisk hydrokarbon, dimetylformamid eller dioksan ved en temperatur fra 40 til 160°C i en reaksjonstid på 1 til 24 timer. Ved omsetningen er det fordelaktig å bruke ekvivalente mengder utgangsmateriale eller et overskudd på 5 til 10 % azetidinol. Ved å tilsette en faseoverførings-katalysator til reaksjonsblandingen i en mengde på 2 til 20 %, som f.eks. tetrabutylammoniumbromid eller hydrogensul-fat, kan reaksjonen fremskyndes og utbyttet kan også bli påvirket. Produktet utvinnes ved å ekstrahere syreaddi-sjonssaltet derav over i vann og ved å ekstrahere den frigjorte base ved hjelp av et alkalisk middel over i et organisk oppløsningsmiddel og ved å inndampe oppløsningsmid-let. R,S-timolol-basen som fåes i et utbytte på ca. 70 %, kan renses ved krystallisering eller ved overføring til det ønskede syreaddisjonssalt, slik som hydrokloridet eller hydrogenmaleatet. Det skal legges merke til at selv om også en N-substitusjonsreaksjon er mulig under reaksjonsbetingel-sene på grunn av tautomerismen til 3-hydroksy-l,2,5-tiadiazo-ler ved omsetningen ifølge det ovenstående reaksjonsskjerna, er den primære reaksjon blitt påvist å være O-substitusjonen. De små mengder biprodukter som dannes ved N-substitusjonen kan lett hydrolyseres ved å tilsette vann ved slutten av omsetningen og å fortsette tilbakeløpskokingen i 1 til 3 timer deretter, hvorved hydrolysen av det N-substituerte biprodukt finner sted kvantitativt og dette påvirker ikke utvinningen eller rensingen av produktet under de anvendte betingelser. The reaction is preferably carried out in an inert organic solvent such as e.g. benzene, toluene, xylene, chlorinated aliphatic or aromatic hydrocarbon, dimethylformamide or dioxane at a temperature from 40 to 160°C for a reaction time of 1 to 24 hours. In the reaction, it is advantageous to use equivalent amounts of starting material or an excess of 5 to 10% azetidinol. By adding a phase transfer catalyst to the reaction mixture in an amount of 2 to 20%, such as tetrabutylammonium bromide or hydrogen sulphate, the reaction can be accelerated and the yield can also be affected. The product is recovered by extracting the acid addition salt thereof into water and by extracting the liberated base with the aid of an alkaline agent into an organic solvent and by evaporating the solvent. The R,S-timolol base which is obtained in a yield of approx. 70%, can be purified by crystallization or by transfer to the desired acid addition salt, such as the hydrochloride or hydrogen maleate. It should be noted that although an N-substitution reaction is also possible under the reaction conditions due to the tautomerism of 3-hydroxy-1,2,5-thiadiazoles in the reaction according to the above reaction core, the primary reaction has been demonstrated to be the O substitution. The small amounts of by-products formed by the N-substitution can be readily hydrolysed by adding water at the end of the reaction and continuing the reflux for 1 to 3 hours thereafter, whereby the hydrolysis of the N-substituted by-product takes place quantitatively and does not affect recovery or purification of the product under the conditions used.
3-hydroksy-4-morfolino-1,2,5-tiadiazol som anvendes i det ovenstående reaksjonsskjema som et annet utgangsmaterial for fremstillingen av R,S-timolol, kan fremstilles ifølge fremgangsmåter som er kjent fra litteraturen (jfr. f.eks. J. Org. Chem. 41, 3121 (1976) og J. Org. Chem. 32, 2823 (1963) og DE patentskrift nr. 1.914.496) og angis ikke her mer detaljert. 3-Hydroxy-4-morpholino-1,2,5-thiadiazole, which is used in the above reaction scheme as another starting material for the production of R,S-timolol, can be prepared according to methods known from the literature (cf. e.g. J. Org. Chem. 41, 3121 (1976) and J. Org. Chem. 32, 2823 (1963) and DE Patent No. 1,914,496) and are not stated here in more detail.
Eksempel 1 Example 1
Fremstilling av racemisk diacetvl- L- vinsvre- Q- monoester av R, S- morfolino- 4-( 3'- tert- butvlamino- 2'- hydroksypropoksy)-1. 2. 5- tiadiazol. Preparation of racemic diacetyl-L-tartaric acid-Q-monoester of R,S-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1. 2. 5- Thiadiazole.
A) ?:_§I3I™0:£f °lino~4~ (3 ' -tert-butylamino-2 '_-hydroksypropok-sy)_-lL2, 5-tiadiazol _(= R, S-timolol)_ A) ?:_§I3I™0:£f °lino~4~ (3 '-tert-butylamino-2 '_-hydroxypropoxy)_-lL2, 5-thiadiazole _(= R, S-timolol)_
93,6 g (0,5 mol) 3-hydroksy-4-morfolino-1,2,5-tiadiazol ble 93.6 g (0.5 mol) of 3-hydroxy-4-morpholino-1,2,5-thiadiazole was
blandet med 7 50 ml toluen og til blandingen ble det dråpevis tilsatt 90 g av en 30 % oppløsning av natriummetylat i løpet av en tidsperiode på ca. 10 minutter. Etter tilsetningen ble det fortsatt blandet i ytterligere 10 minutter og 91 g (0,55 mol) l-tert-butyl-3-azetidinolhydroklorid og 8,5 g (0,025 mixed with 750 ml of toluene and to the mixture 90 g of a 30% solution of sodium methylate was added dropwise over a time period of approx. 10 minutes. After the addition, mixing was continued for another 10 minutes and 91 g (0.55 mol) of 1-tert-butyl-3-azetidinol hydrochloride and 8.5 g (0.025
mol) tetrabutylammoniumhydrogensulfat ble tilsatt. Blandingen ble oppvarmet til koking og destillert inntil temperatu-ren var ca. 90°C, hvoretter den ble omrørt under tilbakeløp i 10 timer. 100 ml vann ble tilsatt- og blandingen ble omrørt under tilbakeløpskoking i ytterligere 2 timer og avkjølt, og 800 ml 3N saltsyre ble tilsatt ved en temperatur som var mindre enn 20°C. Blandingen ble filtrert og den vandige fase i filtratet gjort alkalisk med en konsentrert natriumhydrok-sydoppløsning ved en temperatur som var mindre enn 20°C. Blandingen ble ekstrahert med 500 ml metylenklorid og ekstraktet ble tørket og inndampet til tørrhet under vakuum. Den oljeaktige R,S-timolol-basen som ble erholdt som mol) of tetrabutylammonium hydrogen sulfate was added. The mixture was heated to boiling and distilled until the temperature was approx. 90°C, after which it was stirred under reflux for 10 hours. 100 ml of water was added and the mixture was stirred under reflux for a further 2 hours and cooled, and 800 ml of 3N hydrochloric acid was added at a temperature less than 20°C. The mixture was filtered and the aqueous phase of the filtrate made alkaline with a concentrated sodium hydroxide solution at a temperature less than 20°C. The mixture was extracted with 500 ml of methylene chloride and the extract was dried and evaporated to dryness under vacuum. The oily R,S-timolol base obtained as
inndampingsresten, ble renset ved utkrystallisering fra en blanding av toluen og heksan, hvorved det ble oppnådd ca. the evaporation residue, was purified by crystallization from a mixture of toluene and hexane, whereby approx.
100 g (63 % av det teoretiske) fargeløs R,S-timolol-base. Innhold 96 % (HPLC). Sm.p. 71-72°C. ^H-NMR (CDCI3): 6 1,1 (s, 9H), 2,4-3,0 (m, 3H), 3,3-4,0 (m, 9H) , 4,3-4,5 (d, 2H, <13>C-NMR (CDCI3): jfr. tabell 1. 100 g (63% of theoretical) colorless R,S-timolol base. Content 96% (HPLC). Sm.p. 71-72°C. 3 H-NMR (CDCl 3 ): δ 1.1 (s, 9H), 2.4-3.0 (m, 3H), 3.3-4.0 (m, 9H), 4.3-4, 5 (d, 2H, <13>C-NMR (CDCl3): cf. table 1.
IR (KBr-tablett): 3280, 3120, 3015, 2950, 2910, 2850, 1525, 1490, 1445, 1415, 1375, 1360, 1325, 1310, 1290, 1255, 1220, 1170, 1120, 1110, 1060, 1022, 990, 940, 920, 900, 850 cm-<1>. IR (KBr tablet): 3280, 3120, 3015, 2950, 2910, 2850, 1525, 1490, 1445, 1415, 1375, 1360, 1325, 1310, 1290, 1255, 1220, 1170, 1120, 10120, 10120 , 990, 940, 920, 900, 850 cm-<1>.
Utgangsmaterialene som ble brukt kan fremstilles på følgende måte. The starting materials used can be prepared in the following way.
l-tert-butyl-3-azetidinol-hydrqklqrid 1-tert-butyl-3-azetidinol hydrochloride
92,5 g (1 mol) epiklorhydrin ble oppløst i 200 ml etanol og til oppløsningen ble det dråpevis tilsatt 73,1 g (- mol) tert-butylamin under omrøring i løpet av et tidsrom på ca. 1 time. Etter at den eksoterme reaksjon var avsluttet ble blandingen kokt under tilbakeløp i 1 time hvoretter etanolen ble fradestillert inntil 90 %. Til resten ble det tilsatt ca. 200 ml aceton og omrøringen ble fortsatt i 3 timer. Det utkrystalliserte produkt ble frafiltrert og vasket med aceton og rekrystallisert fra isopropanol. Utbyttet var ca. 83 g (50 % av det teoretiske) av fargeløst l-tert-butyl-3-azetidinol-hydroklorid. Innhold (HPCL) > 96 %. Sm.p. 157-158°C. 92.5 g (1 mol) of epichlorohydrin was dissolved in 200 ml of ethanol and 73.1 g (- mol) of tert-butylamine was added dropwise to the solution with stirring over a period of approx. 1 hour. After the exothermic reaction had ended, the mixture was boiled under reflux for 1 hour, after which the ethanol was distilled off until 90%. To the rest was added approx. 200 ml of acetone and stirring was continued for 3 hours. The crystallized product was filtered off and washed with acetone and recrystallized from isopropanol. The yield was approx. 83 g (50% of theory) of colorless 1-tert-butyl-3-azetidinol hydrochloride. Content (HPCL) > 96%. Sm.p. 157-158°C.
^H-NMR (CDCI3): 5 1,4 (s, 9H), 4,1 (kvintet, 4H), 4,4-5,0 3 H-NMR (CDCl 3 ): δ 1.4 (s, 9H), 4.1 (quintet, 4H), 4.4-5.0
(m, 1H) , 5,9 (br.s, 1H) . (m, 1H) , 5.9 (br.s, 1H) .
3-hydroksy-4-morfolino-1,2,5-tiadiaz<q>l 3-Hydroxy-4-morpholino-1,2,5-thiadiaz<q>l
a. 3-isopropoksy-4-morfolino-1,2,5-tiadiazol 17,9 g (0,1 mol) 3-isopropoksy-4-klor-l,2,5-tiadiazol ble oppløst i 65 ml morfolin og blandingen ble omrørt i 16 timer ved 100-110°C, hvoretter overskuddet av morfolin ble fradestillert under vakuum. Til resten ble 100 ml metylenklorid tilsatt og den uoppløste delen ble fraskilt ved filtrering. Filtratet ble vasket med IN saltsyre og vann, tørket på magnesiumsulfat og filtrert. Filtratet ble inndampet til tørrhet under vakuum hvorved man fikk 3- a. 3-isopropoxy-4-morpholino-1,2,5-thiadiazole 17.9 g (0.1 mol) of 3-isopropoxy-4-chloro-1,2,5-thiadiazole was dissolved in 65 ml of morpholine and the mixture was stirred for 16 hours at 100-110°C, after which the excess of morpholine was distilled off under vacuum. To the residue was added 100 ml of methylene chloride and the undissolved part was separated by filtration. The filtrate was washed with IN hydrochloric acid and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness under vacuum, whereby 3-
isopropoksy-4-morfolino-1,2,5-tiadiazol som en gul, sakte krystalliserende olje. Utbyttet var 90 til 95 % av det teoretiske. isopropoxy-4-morpholino-1,2,5-thiadiazole as a yellow, slowly crystallizing oil. The yield was 90 to 95% of the theoretical.
<1>H-NMR (CDC13): 6 1,4-1,5 (d, 6H), 3,4-3,9 (m, 8H), 4,9-5,4 <1>H-NMR (CDCl 3 ): δ 1.4-1.5 (d, 6H), 3.4-3.9 (m, 8H), 4.9-5.4
(m, 1H) (m, 1H)
b. 3-hydroksy-4-morfolino-1,2,5-tiadiazol 22,9 g (0,1 mol) 3-isopropoksy-4-morfolino-1,2,5-tiadiazol ble oppløst i 400 ml 1,2-dikloretan og under omrøring og avkjøling ble 75 g (0,4 mol) titantetraklorid tilsatt. Blandingen ble omrørt under tilbakeløpskoking i 20 timer og mens den ble avkjølt, ble 80 ml vann tilsatt. Den vandige fase ble gjort alkalisk med en 20 % oppløsning av natrium-hydroksyd, vann ble tilsatt og det ble omrørt og filtrert. Filtratet ble surgjort med saltsyre, hvorved 3-hydroksy-4-morfolino-1,2,5-tiadiazolet ble utfelt. Produktet ble fraskilt ved filtrering og vasket med vann og tørket. Utbyttet var ca. 12,5 g (67 % av det teoretiske) av et lyst brunt produkt som ble rekrystallisert fra absolutt etanol, sm.p. 197-199°C. b. 3-hydroxy-4-morpholino-1,2,5-thiadiazole 22.9 g (0.1 mol) of 3-isopropoxy-4-morpholino-1,2,5-thiadiazole was dissolved in 400 ml of 1,2 -dichloroethane and, while stirring and cooling, 75 g (0.4 mol) of titanium tetrachloride were added. The mixture was stirred under reflux for 20 hours and while cooling, 80 ml of water was added. The aqueous phase was made alkaline with a 20% solution of sodium hydroxide, water was added and it was stirred and filtered. The filtrate was acidified with hydrochloric acid, whereby the 3-hydroxy-4-morpholino-1,2,5-thiadiazole was precipitated. The product was separated by filtration and washed with water and dried. The yield was approx. 12.5 g (67% of theory) of a light brown product which was recrystallized from absolute ethanol, m.p. 197-199°C.
<1->H-NMR ((CD3)2SO): 5 3,2-4,0 (m, 8H) . <1->H-NMR ((CD 3 ) 2 SO): δ 3.2-4.0 (m, 8H).
B) Fremstilling_av den_racemiske_diacetyl-L-vinsyre-0-monoester av_R,S-3-morfolino-4-(3'-tert-butylaminq-21 - B) Preparation_of_the_racemic_diacetyl-L-tartaric-0-monoester of_R,S-3-morpholino-4-(3'-tert-butylamineq-21 -
hydroksypropoksy)-1,2,5-tiadiazol hydroxypropoxy)-1,2,5-thiadiazole
108 g (0,5 mol) diacetyl-L-vinsyreanhydrid (fremstilling: "Organic Synthesis", Coll. vol. IV, 2. utgave 1967, s. 242, "Substituting D-Tartaric acid with L-tartaric acid") ble oppløst i 750 ml metylenklorid og til oppløsningen ble det dråpevis tilsatt under omrøring 158 g (0,5 mol) av R,S-timolol-base i 350 ml metylenklorid i løpet av 10 til 15 minutter ved værelsestemperatur, og det ble inndampet til tørrhet under vakuum. Utbyttet var 266 g (100 % av det teoretiske) ren diacetyl-L-vinsyre-O-monoester av R,s-morfolino-4-(3'-tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol. 108 g (0.5 mol) of diacetyl-L-tartaric anhydride (preparation: "Organic Synthesis", Coll. vol. IV, 2nd edition 1967, p. 242, "Substituting D-Tartaric acid with L-tartaric acid") was dissolved in 750 ml of methylene chloride and to the solution was added dropwise with stirring 158 g (0.5 mol) of R,S-timolol base in 350 ml of methylene chloride over 10 to 15 minutes at room temperature and evaporated to dryness under vacuum. The yield was 266 g (100% of theory) of pure diacetyl-L-tartaric acid-O-monoester of R,s-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5- thiadiazole.
<1>H-NMR (CDCI3): 6 1,5 (s, 9H), 2,1-2,2 (d, 6H), 3,0-4,0 (m, 10H), 4,3-5,8 (m, 5H). <1>H-NMR (CDCl3): 6 1.5 (s, 9H), 2.1-2.2 (d, 6H), 3.0-4.0 (m, 10H), 4.3- 5.8 (m, 5H).
1<3>C-NMR ((CD3)2SO + (C<D>3)2CO): jfr. tabell 1. 1<3>C-NMR ((CD3)2SO + (C<D>3)2CO): cf. table 1.
IR (KBr-tablett): 3420, 2970, 2840, 1745, 1635, 1530, 1495, 1445, 1370, 1310, 1290, 1255, 1220, 1115, 1060, 970, 950, IR (KBr tablet): 3420, 2970, 2840, 1745, 1635, 1530, 1495, 1445, 1370, 1310, 1290, 1255, 1220, 1115, 1060, 970, 950,
925 cm-1.925 cm-1.
MS (Cl, I-butan): M+57 589, M+l 533, 317, 86 MS (Cl, I-butane): M+57 589, M+1 533, 317, 86
MS (EI, 70 EV): 517, 386, 130, 86 MS (EI, 70 EV): 517, 386, 130, 86
Det er denne racemiske monoester som er et egnet utgangsprodukt for fremstillingen av S-timolol ved en fremgangsmåte som er omhandlet i Norsk utlegn.skrift 158.020. It is this racemic monoester which is a suitable starting product for the production of S-timolol by a method which is discussed in Norwegian Publication No. 158.020.
Eksempel 2 Example 2
Fremstilling av racemisk dibenzovl- L- vinsvre- O- monoester av R. S- 3- morfolino- 4-( 3'- tert- butvlamino- 2'- hydroksypropoksy)-1. 2. 5- tiadiazol Preparation of racemic dibenzoyl-L-tartaric acid-O-monoester of R.S-3-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1. 2. 5- Thiadiazole
Dibenzoyl-L-vinsyre-O-monoesteren av R,S-2-morfolino-4-(3'-tert-butylamino-2'-hydroksypropoksy)-1,2,5-tiadiazol ble fremstilt i henhold til eksempel 1, men i stedet for diacetyl-L-vinsyreanhydrid ble det brukt dibenzoyl-L-vinsyreanhydrid (fremstilling ifølge J.A. Chem. Soc. 55 2605 The dibenzoyl-L-tartaric acid-O-monoester of R,S-2-morpholino-4-(3'-tert-butylamino-2'-hydroxypropoxy)-1,2,5-thiadiazole was prepared according to Example 1, but instead of diacetyl-L-tartaric anhydride, dibenzoyl-L-tartaric anhydride was used (preparation according to J.A. Chem. Soc. 55 2605
(1933) "Substituting D-tartaric acid with L-tartaric acid"). Utbytte av rent produkt var 312 g (100 % av det teoretiske). <1>H-NMR ((CDCI3): 6 1,1-1,5 (2s, 9H), 2,8-4,0 (m, 10H), 4,2-5,0 (s, 2H), 5,0-5,9 (m, 3H), 7,0-8,3 (m, 10H) (1933) "Substituting D-tartaric acid with L-tartaric acid"). Yield of pure product was 312 g (100% of theoretical). <1>H-NMR ((CDCl3): δ 1.1-1.5 (2s, 9H), 2.8-4.0 (m, 10H), 4.2-5.0 (s, 2H) , 5.0-5.9 (m, 3H), 7.0-8.3 (m, 10H)
<13>C-NMR ((CD3)2SO <+> (CD3)2CO): jfr. tabell 1. <13>C-NMR ((CD3)2SO <+> (CD3)2CO): cf. table 1.
IR (KBr-tablett): 3410, 3050, 3025, 2960, 2840, 1760, 1720, 1640, 1600, 1560, 1530, 1500, 1445, 1380, 1370, 1310, 1290, 1255, 1170, 1110, 1065, 1020, 1000, 950 cm<-1>. IR (KBr tablet): 3410, 3050, 3025, 2960, 2840, 1760, 1720, 1640, 1600, 1560, 1530, 1500, 1445, 1380, 1370, 1310, 1290, 1255, 1170, 10150, 10150 , 1000, 950 cm<-1>.
Denne racemiske monoester er også egnet for anvendelse som utgangsprodukt for fremstilling av S-timolol ved den fremgangsmåte som er omhandlet i Norsk utlegn.skrift 15 8.020. This racemic monoester is also suitable for use as a starting product for the production of S-timolol by the method referred to in Norsk ulegn.skrift 15 8.020.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO870919A NO165024C (en) | 1984-03-30 | 1987-03-05 | L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5 - THIADIAZOLE. |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI841292A FI71933C (en) | 1984-03-30 | 1984-03-30 | New L-tartaric acid O-monoesters of 3-morpholino-4- (3'-tert.-butylamino-2'-hydroxypropoxy) -1,2,5-thiadiazole and their use as intermediates. |
NO851307A NO158020C (en) | 1984-03-30 | 1985-03-29 | PROCEDURE FOR THE PREPARATION OF OPTICALLY PURE S-3-MORPHOLINO-4- (3'-TERTBUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5-THIADIAZOLE |
NO870919A NO165024C (en) | 1984-03-30 | 1987-03-05 | L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5 - THIADIAZOLE. |
Publications (4)
Publication Number | Publication Date |
---|---|
NO870919L NO870919L (en) | 1985-10-01 |
NO870919D0 NO870919D0 (en) | 1987-03-05 |
NO165024B true NO165024B (en) | 1990-09-03 |
NO165024C NO165024C (en) | 1990-12-12 |
Family
ID=27241113
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO870919A NO165024C (en) | 1984-03-30 | 1987-03-05 | L-TIN ACID O-MONOESTERS OF 3-MORPHOLINO-4- (3'-TERT-BUTYLAMINO-2'-HYDROXYPROPOXY) -1,2,5 - THIADIAZOLE. |
Country Status (1)
Country | Link |
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NO (1) | NO165024C (en) |
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1987
- 1987-03-05 NO NO870919A patent/NO165024C/en unknown
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Publication number | Publication date |
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NO870919D0 (en) | 1987-03-05 |
NO870919L (en) | 1985-10-01 |
NO165024C (en) | 1990-12-12 |
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