NO135903B - - Google Patents
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- NO135903B NO135903B NO2163/72A NO216372A NO135903B NO 135903 B NO135903 B NO 135903B NO 2163/72 A NO2163/72 A NO 2163/72A NO 216372 A NO216372 A NO 216372A NO 135903 B NO135903 B NO 135903B
- Authority
- NO
- Norway
- Prior art keywords
- penicillamine
- norephedrine
- formyl
- mol
- carboxylic acid
- Prior art date
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- 229960001639 penicillamine Drugs 0.000 claims description 28
- DLNKOYKMWOXYQA-CBAPKCEASA-N (-)-norephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-CBAPKCEASA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 19
- VVNCNSJFMMFHPL-UHFFFAOYSA-N penicillamine Chemical compound CC(C)(S)C(N)C(O)=O VVNCNSJFMMFHPL-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 230000003287 optical effect Effects 0.000 claims description 5
- 238000011084 recovery Methods 0.000 claims description 2
- 239000011833 salt mixture Substances 0.000 claims description 2
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims 2
- VVNCNSJFMMFHPL-GSVOUGTGSA-N L-penicillamine Chemical compound CC(C)(S)[C@H](N)C(O)=O VVNCNSJFMMFHPL-GSVOUGTGSA-N 0.000 description 29
- 238000003776 cleavage reaction Methods 0.000 description 20
- 230000007017 scission Effects 0.000 description 20
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012452 mother liquor Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 description 6
- 239000011707 mineral Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- -1 D,L-penicillamine amine Chemical class 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010036030 Polyarthritis Diseases 0.000 description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 229960000395 phenylpropanolamine Drugs 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- CZDHUFYOXKHLME-UHFFFAOYSA-N 2-amino-3-methyl-3-sulfanylbutanoic acid;hydron;chloride Chemical compound Cl.CC(C)(S)C(N)C(O)=O CZDHUFYOXKHLME-UHFFFAOYSA-N 0.000 description 1
- QEIKJZZSMZXSAI-UHFFFAOYSA-N 3-formyl-2,2,5,5-tetramethyl-1,3-thiazolidine-4-carboxylic acid Chemical compound CC1(C)SC(C)(C)N(C=O)C1C(O)=O QEIKJZZSMZXSAI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010011778 Cystinuria Diseases 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Tires In General (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Aminosyren D-penicillamin er kjent som virksomt The amino acid D-penicillamine is known to be effective
stoff av betydelige legemidler til behandling av Morbus Wilson, defekt schizofreni, sklerodermi, cystinuri og den kronisk ag-gressive hepatitis, samt til basisterapi av primær kronisk polyartritis. D-penicillamin finner videre anvendelse som antidot ved tungmetallintoksikasjoner. substance of significant drugs for the treatment of Morbus Wilson, defective schizophrenia, scleroderma, cystinuria and the chronic aggressive hepatitis, as well as for basic therapy of primary chronic polyarthritis. D-penicillamine is also used as an antidote for heavy metal intoxications.
En terapeutisk anvendelse kan bare D-penicillamin A therapeutic application can only D-penicillamine
finne, fordi L-isomeren er meget mere toksisk. find, because the L-isomer is much more toxic.
Det er kjent å utvinne D-penicillamin i en om- It is known to recover D-penicillamine in a re-
stendelig hydrolytisk prosess fra penicillin, hvilket i betrakt- constant hydrolytic process from penicillin, which considering
ning av det høyverdige utgangsmaterial forklarer den høye pris på denne aminosyre som hindrer den brede medisinske anvendelse av D-penicillamin, spesielt som basisterapeutikum for permanent-behandling av primær kronisk polyartritis. Av denne grunn til-kommer en totalsyntese for D-penicillamin spesiell betydning. ning of the high-quality starting material explains the high price of this amino acid which prevents the wide medical use of D-penicillamine, especially as a basic therapeutic agent for the permanent treatment of primary chronic polyarthritis. For this reason, a total synthesis for D-penicillamine is of particular importance.
Det er imidlertid også kjent å fremstille D,L-penicillamin syntetisk og herav å utvinne D-penicillamin ved racematspaltning. Som optisk aktive baser anvendes herved d-pseudoefedrin og 1-efedrin ("The Chemistry of Penicilline" However, it is also known to produce D,L-penicillamine synthetically and to extract D-penicillamine from this by racemate cleavage. D-pseudoephedrine and 1-ephedrine are used as optically active bases ("The Chemistry of Penicillin"
(19^9), Princeton University Press, britisk patent nr. 585. 413, US-patent nr. 2.450.784, belgisk patent nr. 738.520). (19^9), Princeton University Press, British Patent No. 585. 413, US Patent No. 2,450,784, Belgian Patent No. 738,520).
Til racematspaltning må D,L-penicillamin overføres For racemate cleavage, D,L-penicillamine must be transferred
i egnede derivater, dvs. i penicillaminmolekylet må, slik det er vanlig ved racematspaltning av aminosyrer innføres beskyt-telsesgrupper. Som til av racematspaltning egnede derivater kommer det eksempelvis på tale N-acyleringsprodukter av D,L-penicillamin resp. av S-benzyl-D,L-penicillamin samt acylerings-produktene av omsetningsproduktene av D,L-penicillamin med kar-bonyl forbindelser. in suitable derivatives, i.e. in the penicillamine molecule, protecting groups must be introduced, as is common with racemate cleavage of amino acids. Derivatives suitable for racemate cleavage include, for example, N-acylation products of D,L-penicillamine or of S-benzyl-D,L-penicillamine as well as the acylation products of the reaction products of D,L-penicillamine with carbonyl compounds.
Disse fremgangsmåter til racematspaltning av D,L-penicillamin er imidlertid lite tilfredsstillende, da ved omsetningen av D,L-penicillaminaminderivatet med de nevnte spalt-baser utfelles det uønskede isalt av L-penicillaminderivat og den optisk aktive hjelpebase. Det er imidlertid kjent at prin-sippielt har den fra reaksjonsoppløsningen utkrystalliserende antipode den større renhet, (H.D. Jakubke und H. Jeschkeit, "Aminosåuren, Peptide, Proteine", Akademie-Verlag, Berlin, 1969, samt L.F. Fieser og M. Fieser, "Lehrbuch der Organischen Chemie", Verlag Chemie, Weinheim, 1957). However, these methods for racemate cleavage of D,L-penicillamine are not satisfactory, as the reaction of the D,L-penicillamine amine derivative with the aforementioned cleavage bases precipitates the unwanted isalt of L-penicillamine derivative and the optically active auxiliary base. It is known, however, that in principle the antipode crystallising from the reaction solution has the greater purity, (H.D. Jakubke und H. Jeschkeit, "Aminosåuren, Peptide, Proteine", Akademie-Verlag, Berlin, 1969, as well as L.F. Fieser and M. Fieser, "Lehrbuch der Organischen Chemie", Verlag Chemie, Weinheim, 1957).
Det er nå funnet at det er spesielt fordelaktig, for utvinning av D-penicillamin fra D,L-penicillamin å anvende 1-norefedrin (fenylpropanolamin) It has now been found that it is particularly advantageous for the recovery of D-penicillamine from D,L-penicillamine to use 1-norephedrine (phenylpropanolamine)
Oppfinnelsen vedrører altså en fremgangsmåte til utvinning av D-penicillamin av D,L-penicillamin ved å overføre racematet til en racemisk N-acyl-2,2-disubstituert-5,5-dimetyl-tiazolidin-4-karboksylsyre som omsettes med en optisk aktiv base til en saltblanding hvorfra saltet av D-N-aeyl-2,2-disub-stituert-5,5-dimetyl-tiazolidin-4-karboksylsyre isoleres og av dette fremstilles D-penicillamin, idet fremgangsmåten er karakterisert ved at den anvendte base er 1-norefedrin. The invention therefore relates to a method for extracting D-penicillamine from D,L-penicillamine by transferring the racemate to a racemic N-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxylic acid which is reacted with an optical active base to a salt mixture from which the salt of D-N-aeyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxylic acid is isolated and D-penicillamine is prepared from this, the method being characterized by the base used being 1-norephedrine.
Racematspaltningen av D,L-penicillamin forløper The racemate cleavage of D,L-penicillamine proceeds
ved hjelp av denne optiske aktive base i høyt utbytte og D-penicillamin fremkommer i høy renhet da det ønskede salt av D-syre og L-base er tyngre oppløselig og faller ut. with the help of this optically active base in high yield and D-penicillamine appears in high purity as the desired salt of D-acid and L-base is more difficult to dissolve and precipitates out.
Som ved de tidligere kjente fremgangsmåter til racematspaltning må også ved fremgangsmåten ifølge oppfinnelsen D,L-penicillamin i første rekke overføres i et for racematspaltning spesielt egnet derivat før omsetningen med 1-norefedrin kan foregå, dvs. at ett eller begge hydrogenatomer av aminogruppen først må beskyttes. Samtidig kan det også foregå en beskyttelse ( kv hydrogen-atomet av merkaptogruppen. Herved kan man fremfor alt gjøre bruk av i og for seg kjente metoder, som eksempelvis er omtalt i "Chemistry of the Amino Acids" J.P. Greenstein og M. Winitz, J, Wiley & Sons, Inc., New York 1961 samt i Houben Weyl, 1958, bind 11/2, Georg Thieme Verlag. En slik beskyttelse kan eksempelvis oppnås ved at man på kjent måte overfører D,L-penicillamin i en forbindelse med den gene-reile formel As with the previously known methods for racemate resolution, also in the method according to the invention D,L-penicillamine must first of all be transferred into a derivative particularly suitable for racemate resolution before the reaction with 1-norephedrine can take place, i.e. one or both hydrogen atoms of the amino group must first be protected. At the same time, a protection can also take place (for the hydrogen atom of the mercapto group. In this way, above all, you can make use of methods known in and of themselves, which are discussed, for example, in "Chemistry of the Amino Acids" J.P. Greenstein and M. Winitz, J , Wiley & Sons, Inc., New York 1961 as well as in Houben Weyl, 1958, volume 11/2, Georg Thieme Verlag. Such protection can be achieved, for example, by transferring D,L-penicillamine in a known manner in a connection with the gene-reile formula
hvori Ac betyr en acylgruppe, spesielt en benzoyl-, tosyl-, nitro-fenylsulfenyl-, acetyl- eller fortrinnsvis en formylgruppe, Z betyr et hydrogenatom, men kan imidlertid også sammen med Ac bety en di-acylrest, spesielt ftalylresten og R betyr et hydrogenatom eller benzylresten og dessuten kan ha samme betydning som Ac. Fortrinnsvis foregår beskyttelsen av slike grupper imidlertid ved at man på kjent måte overfører D,L-penicillamin i en tiazolidin-4-karboksylsyre med den generelle formel 12 .. in which Ac means an acyl group, especially a benzoyl, tosyl, nitro-phenylsulfenyl, acetyl or preferably a formyl group, Z means a hydrogen atom, but can, however, together with Ac also mean a di-acyl residue, especially the phthalyl residue and R means a hydrogen atom or the benzyl residue and can also have the same meaning as Ac. Preferably, however, the protection of such groups takes place by transferring D,L-penicillamine in a known manner into a thiazolidine-4-carboxylic acid with the general formula 12..
hvori R og R er like eller forskjellige og betyr et hydrogenatom eller en alkylrest med 1 til 8 karbonatomer eller en cykloalkyl-eller arylrest og Ac har overnevnte betydning. wherein R and R are the same or different and mean a hydrogen atom or an alkyl residue with 1 to 8 carbon atoms or a cycloalkyl or aryl residue and Ac has the above meaning.
Blant disse beskyttede forbindelser ér igjen de fore-trukket som fåes ved overføring av D,L-penicillamin i et N-acetyl-eller fortrinnsvis N-formylderivat av en 2,2-dialkyl-5,5-dimetyl-tiazolidin-4-karboksylsyre. Blant disse utmerker det seg igjen N-formy1-2,2,5,5-tetrametyl-tiazolidin-4-karboksylsyre (N-formy1-isopropyliden-D,L-penicillamin). Disse tiazolidin-4-karboksylsyrer kan fremstilles på enkel måte av D,L-penicillamin og de tilsvarende kar-bonylforbindelser (The Chemistry of Penicilline (1949), Princeton University Press). Overføringen i N-acyl-forbindelsene kan i for-bindelsen med beskyttet merkaptogruppe er omtalt i samme literatur-sted .• Among these protected compounds, those obtained by transferring D,L-penicillamine into an N-acetyl or preferably N-formyl derivative of a 2,2-dialkyl-5,5-dimethyl-thiazolidine-4-carboxylic acid are again preferred. . Among these, N-formyl-2,2,5,5-tetramethyl-thiazolidine-4-carboxylic acid (N-formyl-isopropylidene-D,L-penicillamine) again stands out. These thiazolidine-4-carboxylic acids can be prepared easily from D,L-penicillamine and the corresponding carbonyl compounds (The Chemistry of Penicillin (1949), Princeton University Press). The transfer in the N-acyl compounds in the connection with a protected mercapto group is described in the same literature site.•
Som oppløsnihgsmiddel kan det ved racematadskillelsen foruten vann fremfor alt anvendes organisk oppløsningsmiddel, f.eks. alkoholer, alifatiske hydrokarboner, halogenerte alifatiske hydrokarboner, etere, ketoner, estére, aromatiske hydrokarboner og lig-nende, fortrinnsvis anvendes tienzen, toluen, isopropanol, dioksan og lavere karboksylsyreestereJ In the racemate separation, in addition to water, an organic solvent, e.g. alcohols, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, ethers, ketones, esters, aromatic hydrocarbons and the like, preferably thiene, toluene, isopropanol, dioxane and lower carboxylic acid esters are used
Ved gjennomføring av fremgangsmåten ifølge oppfinnelsen kan man hensiktsmessig :gå frem således at man overfører D,L-penicillamin på kjent måte i de for racematspaltningen egnede derivater (beskyttet D,L-penicillamin) og oppløser disse i vann eller fortrinnsvis i et organisk oppløsningsmiddel eller oppløsnings-middelblanding og blander denne oppløsningen, eventuelt under oppvarmning med 1-norefedrin, eventuelt oppløst i et organisk oppløs-ningsmiddel, idet det ofte med en gang, under tiden først etter lengre henstand, eventuelt ved lav temperatur og etter podning faller ut det tyngre oppløselig salt av D-pennicillaminderivat og 1-norefedrin, mens det diastereoisomere salt, den optiske antipode og den racemiske blanding resp.' blandinger herav forblir i moderluten. Det tyngre oppløselige salt kan på i og for seg kjent måte f.eks. ved behandling med fortynnet mineralsyre overføres i de mineralsure salter av D-penicillamin. Av de mineralske salter kan det fri D-penicillamin likeledes på i og for seg kjent måte, ved f.eks. ved behandling med baser,settes i frihet. When carrying out the method according to the invention, one can expediently: proceed in such a way that one transfers D,L-penicillamine in a known manner into the derivatives suitable for the racemate cleavage (protected D,L-penicillamine) and dissolves these in water or preferably in an organic solvent or solvent mixture and mixes this solution, optionally while heating with 1-norephedrine, optionally dissolved in an organic solvent, as often immediately, in the meantime only after a longer period of time, optionally at a low temperature and after inoculation, the heavier precipitates soluble salt of D-pennicillamine derivative and 1-norephedrine, while the diastereoisomeric salt, the optical antipode and the racemic mixture resp.' mixtures thereof remain in the mother liquor. The heavier soluble salt can in a manner known per se e.g. when treated with diluted mineral acid is transferred into the mineral acid salts of D-penicillamine. Of the mineral salts, free D-penicillamine can also be obtained in a manner known per se, by e.g. when treated with bases, is set free.
Man kan imidlertid også gå frem omvendt og blande oppløsningen av 1-norefedrin med derivatet av det racemiske penicillamin, som fortrinnsvis er oppløst i et organisk oppløsningsmiddel. However, one can also proceed in reverse and mix the solution of 1-norephedrine with the derivative of the racemic penicillamine, which is preferably dissolved in an organic solvent.
Fremgangsmåten ifølge oppfinnelsen kan fortrinnsvis gjennomføres under anvendelse av 0,1 til 3 mol, fortrinnsvis o,5 The method according to the invention can preferably be carried out using 0.1 to 3 mol, preferably o.5
til 1,1 mol 1-norefedrin, pr. mol racemat. I alle områder faller det tyngre oppløselige salt av D-penicillamin-derivat og 1-norefedrin ut. Denne utfelling er ved overholdelse omtrent støkiometriske mengder omtrent kvantitativ. Ved anvendelse av'mindre enn 0,5 mol 1-norefedrin forblir moderluten racemat og optisk antipode, anvender man pr. mol racemat o,5 og under» 1 mol spaltbase, inneholder moderluten foruten den optiske antipode dessuten diastereomert salt. to 1.1 mol 1-norephedrine, per moles of racemate. In all areas, the more soluble salt of D-penicillamine derivative and 1-norephedrine precipitates out. This precipitation is approximately quantitative by observing approximately stoichiometric amounts. When using less than 0.5 mol of 1-norephedrine, the mother liquor remains racemate and optical antipode. 0.5 mol of racemate and less than 1 mol of cleavage base, the mother liquor contains, in addition to the optical antipode, a diastereomeric salt.
i in
Anvender man pr. mol racemat mer enn 1 mol optisk aktive hjelpebase, så inneholder moderluten ved siden av diastereomert salt, dessuten spaltbase. If you use per mol of racemate more than 1 mol of optically active auxiliary base, then the mother liquor contains, in addition to the diastereomeric salt, also cleavage base.
De ved omsetningen dannede salter av penicillamin-derivatet av 1-norefedrin, kan på grunn av meget gunstig oppløselig-hetsforhold på i og for seg kjent måte, utvinnes i ren form, f.eks. ved filtrering, inndampning av moderluten og rensning ved omkrystallisering. The salts of the penicillamine derivative of 1-norephedrine formed during the reaction can, due to very favorable solubility conditions, be recovered in a pure form in a manner known per se, e.g. by filtration, evaporation of the mother liquor and purification by recrystallization.
I ethvert tilfelle faller ved racematspaltningen i første rekke det tyngre oppløselige salt av D-penicillamin-derivat og 1-norefedrin ut, mens den andre diastereomere forblir i oppløs-ning. Dette var meget overraskende, såvel ved anvendelse av D-pseudoefedrin som også 1-efedrinsaltet av L-penicillinamin-derivatet og spaltbasen ér tyngre oppløselig. In any case, during the racemate cleavage, primarily the more soluble salt of D-penicillamine derivative and 1-norephedrine precipitates out, while the other diastereomer remains in solution. This was very surprising, both when using D-pseudoephedrine and also the 1-ephedrine salt of the L-penicillinamine derivative and the split base is more difficult to dissolve.
Spaltningen av det tyngre oppløselige salt foretas likeledes på i og for seg kjent måte ved behandling med fortrinnsvis vandige mineralsyrer, eksempelvis fortynnet saltsyre, idet første rekke spaltbasen tilbakevinnes i form av mineralsurt salt og D-penicillamin-derivatet fåes. The cleavage of the more soluble salt is likewise carried out in a manner known in and of itself by treatment with preferably aqueous mineral acids, for example diluted hydrochloric acid, with the primary cleavage base being recovered in the form of a mineral acid salt and the D-penicillamine derivative being obtained.
Spaltingen av D-penicillamin-derivatet foregår igjen på i og for seg kjent måte ved avspaltning av beskyttelsesgruppene, f.eks. avbenzylering eller sur hydrolyse. The cleavage of the D-penicillamine derivative again takes place in a manner known per se by cleavage of the protective groups, e.g. debenzylation or acid hydrolysis.
På analog måte kan det av moderluten fra racematspaltningen utvinnes L-penicillamin. Som spesielt fordelaktig viser det seg imidlertid på i og for seg kjent måte å racemisere L-penicillamin-derivatet, eventuelt utvinne ved mineralsur spaltning av dets salt med den optiske aktive spaltbase, hvorved det er mulig med en kretsløpsføring av det terapeutisk ikke anvendbare L-penicillamin . In an analogous way, L-penicillamine can be recovered from the mother liquor from the racemate cleavage. However, it turns out to be particularly advantageous to racemize the L-penicillamine derivative in a manner known per se, possibly extracting it by mineral acid cleavage of its salt with the optically active cleaving base, whereby it is possible to circulate the therapeutically unusable L- penicillamine.
Eksempel 1. Example 1.
I et 50 liters glassreaksjonskar, utstyrt med rører, tilbakeløpskjøler, dryppetrakt, gassinnføringsrør og bunnuttaksventil oppløses 3,26 kg (15 mol) N-formyl-isopropyliden-D,L-penicillamin, oppnådd ved omsetning av 3 kg D,L-penicillamin-hydroklorid (16 mol) méd 2,8 kg aceton (50 mol) og etterfølgende formulering med en blanding av maursyre og acetanhydrid under samtidig nøytralisering med natriumacetat,i 20 1 eddikester under oppvarmning ved 50°C. In a 50 liter glass reaction vessel, equipped with stirrer, reflux condenser, dropping funnel, gas inlet pipe and bottom outlet valve, dissolve 3.26 kg (15 mol) of N-formyl-isopropylidene-D,L-penicillamine, obtained by reacting 3 kg of D,L-penicillamine- hydrochloride (16 mol) with 2.8 kg of acetone (50 mol) and subsequent formulation with a mixture of formic acid and acetic anhydride during simultaneous neutralization with sodium acetate, in 20 1 of acetic ester while heating at 50°C.
Til denne oppløsning har man under omrøring og ytterligere oppvarmning 3,28 kg (1,05 x 15 mol) 1-norefedrin, oppløst i 7 1 eddikester, idet det er å iaktta en temperaturøkning rundt ca. 5°C. Etter noen minutter faller det ut adduktet (I) av N-formyl-isopropyliden-D-penicillamin og 1-norefedrin. Under oppvarmning under tilbakeløp etteromrører man ennu en halv time. Etter avkjøling frasuger man godt, vasker med ca. 3 liter eddikester og tørker filterresiduet under nedsatt trykk ved ca. 50°C. Man får 2,75 kg s 98% addukt (I) To this solution, 3.28 kg (1.05 x 15 mol) of 1-norephedrine, dissolved in 7 1 of acetic acid, is added to this solution while stirring and further heating, as a temperature increase around approx. 5°C. After a few minutes, the adduct (I) of N-formyl-isopropylidene-D-penicillamine and 1-norephedrine precipitates out. While heating under reflux, stir for another half hour. After cooling, vacuum well, wash with approx. 3 liters of vinegar and dries the filter residue under reduced pressure at approx. 50°C. You get 2.75 kg of 98% adduct (I)
av smeltepunkt 200-204°C CaJ^ <=><+> 33°. of melting point 200-204°C CaJ^ <=><+> 33°.
Fra moderluten får man etter avdampningen til tørrhet rått addukt (II) av N-formyl-isopropyliden-L-penicillamin og 1-norefedrin, hvorfra det rene addukt av smeltepunkt 116°C og / J~ ol7^ = -74,6° kan utvinnes ved omkrystallisering fra isopropanol. From the mother liquor, after evaporation to dryness, crude adduct (II) of N-formyl-isopropylidene-L-penicillamine and 1-norephedrine is obtained, from which the pure adduct of melting point 116°C and / J~ ol7^ = -74.6° can is recovered by recrystallization from isopropanol.
2,75 kg addukt (I) blandes ved 25°C i rekkefølge med 10 liter destillert vann og 1 liter konsentrert saltsyre. Etter 1 times omrøring frasuger man godt, ettervasker med 2 liter destillert vann og tørker residuet ved 50°C under nedsatt trykk. Man får 1,49 kg = 2.75 kg of adduct (I) are mixed at 25°C in sequence with 10 liters of distilled water and 1 liter of concentrated hydrochloric acid. After stirring for 1 hour, suction well, wash with 2 liters of distilled water and dry the residue at 50°C under reduced pressure. You get 1.49 kg =
92% N-formyl-isopropyliden-D-penicillamin av smeltepunkt 183-184°C 92% N-formyl-isopropylidene-D-penicillamine of melting point 183-184°C
og l_ oi/ D = +53°. Fra moderluten fremkommer etter avdampning til tørrhet omkrystallisering fra isopropanol 1,19 kg 1-norefedrin.HC1 and l_ oi/ D = +53°. From the mother liquor, after evaporation to dryness, recrystallization from isopropanol 1.19 kg 1-norephedrine.HC1
av smeltepunkt 172-174°C. of melting point 172-174°C.
1,49 kg N-formyl-isopropyliden-D-penicillamin haes til 1.49 kg of N-formyl-isopropylidene-D-penicillamine are added
9,0 liter 15#-ig saltsyre som er oppvarmet til 70°C. Etter avdestil-lering av frigjort aceton oppvarmér man ennu i 2 timer ved samme temperatur. Etter avdampning til tørrhet i en 50 liters rotasjons-fordamper får man 1,08 kg rått D-penicillamin.HC1. 9.0 liters of 15# hydrochloric acid which has been heated to 70°C. After the freed acetone has been distilled off, it is heated for a further 2 hours at the same temperature. After evaporation to dryness in a 50 liter rotary evaporator, 1.08 kg of crude D-penicillamine.HC1 is obtained.
1,08 kg D-penicillamin.HC1 oppløses i 8,7 liter 96%-ig alkohol og blandes med 0,59 kg (5»82 mol) trietylamin, idet det fri D-penicillamin utfaller. Etter frasugning, ettervasking med 96%-ig alkohol og tørkning under nedsatt trykk ved 50°C får man 0,78 kg D-penicillamin av smeltepunkt 212-2l4°C og /~a7p° ~"62,8°. 1.08 kg of D-penicillamine.HCl is dissolved in 8.7 liters of 96% alcohol and mixed with 0.59 kg (5.82 mol) of triethylamine, the free D-penicillamine being precipitated. After extraction, subsequent washing with 96% alcohol and drying under reduced pressure at 50°C, 0.78 kg of D-penicillamine of melting point 212-214°C and /~a7p° ~"62.8° is obtained.
Opparbeidelsen av det rå addukt (II) foregår på analog The preparation of the crude adduct (II) takes place analogously
måte som opparbeidelsen av addukt (I). Man får 1,3 kg N-formyl-isopropyliden-l-penicillamin av smeltepunkt l82-l84°C og /_ ujr^ -53°. way as the processing of adduct (I). 1.3 kg of N-formyl-isopropylidene-1-penicillamine of melting point 182-184°C and /_ uj^ -53° is obtained.
1,3 kg N-formyl-isopropyliden-L-penicillamin oppløses i 1.3 kg of N-formyl-isopropylidene-L-penicillamine is dissolved in
4,5 liter toluen og blandes med 30 ml eddiksyreanhydrid. Denne blanding oppvarmes 2 timer under tilbakeløp. Etter avkjøling til værelses-temperatur utkrystalliserer rent N-formyl-isopropyliden-D,L-penicillamin. Man får 1,25 kg N-formyl-isopropyliden-D,L-penicillamin av smeltepunkt 140-142°C og CaT^ 0°, 4.5 liters of toluene and mixed with 30 ml of acetic anhydride. This mixture is heated for 2 hours under reflux. After cooling to room temperature, pure N-formyl-isopropylidene-D,L-penicillamine crystallizes out. 1.25 kg of N-formyl-isopropylidene-D,L-penicillamine of melting point 140-142°C and CaT^ 0° is obtained,
i in
Eksempel 2. Example 2.
I en 1 liters flerhalset kolbe, utstyrt med rører, dryppetrakt, gassinnføringsrør og tilbakeløpskjøler oppløses 43,5 g (032 mol) N-formyl-isopropyliden-D,L-penicillamin i 300 ml eddikester under oppvarmning ved 50°C. Til denne oppløsninghar man porsjons-vis i løpet av 5 minutter 16,7 g (0,11 mol) 1-norefedrin og oppvarmer etter 30 minutter under tilbakeløp. Etter avkjøling til værelses-temperatur frasuger man godt, ettervasker med 150 ml eddikester og tørker under nedsatt trykk ved 50°C. Man får 33,9 g = 92$-N-formyl- - isopropyliden-D-penicillamin-l-norefedrin addukt I. av smeltepunkt 202-204°C og _/<->a7^° = +31°. Adduktets spalter foregår som omtalt i eksempel 1. Man får 10 g D-penicillamin av smeltepunkt 212-214°<J °g L~^ 7l° -62,7°. In a 1 liter multi-necked flask, equipped with a stirrer, dropping funnel, gas introduction tube and reflux condenser, 43.5 g (032 mol) of N-formyl-isopropylidene-D,L-penicillamine are dissolved in 300 ml of acetic acid while heating at 50°C. To this solution, 16.7 g (0.11 mol) of 1-norephedrine are added in portions over the course of 5 minutes and heated under reflux after 30 minutes. After cooling to room temperature, suction well, wash with 150 ml of vinegar and dry under reduced pressure at 50°C. 33.9 g = 92$-N-formyl- - isopropylidene-D-penicillamine-l-norephedrine adduct I. of melting point 202-204°C and _/<->a7^° = +31° is obtained. The cleavage of the adduct takes place as described in example 1. 10 g of D-penicillamine of melting point 212-214°<J °g L~^ 7l° -62.7° is obtained.
Eksempel 3- Example 3-
Man går frem som omtalt i eksempel 2 og anvender imidlertid isopropylalkohol som oppløsningsmiddel. Man får 33,1 g ( 905?) av adduktet, hvorfra det ved spaltning fåes 9,7 g D-penicillamin av smeltepunkt 211-213°C og £~ 1^ ° = -62,7°. Proceed as described in example 2, but use isopropyl alcohol as solvent. 33.1 g (905?) of the adduct is obtained, from which 9.7 g of D-penicillamine of melting point 211-213°C and £~ 1^ ° = -62.7° is obtained by cleavage.
Eksempel 4. Example 4.
Man går frem som omtalt i eksempel 2 og anvender imidlertid toluen som oppløsningsmiddel. Man får 32 g (87$) av addukt I One proceeds as described in example 2 and, however, uses toluene as solvent. 32 g (87$) of adduct I is obtained
og smeltepunkt 201-202°C og Z~£~d° ="31,8°. and melting point 201-202°C and Z~£~d° ="31.8°.
Eksempel 5- Example 5-
Man går frem som omtalt i eksempel 1, går imidlertid ut fra 21,8 g (0,1 mol) N-formyl-isopropyliden-D,,L-penicillamin og 15,1 g (0,1 mol) 1-norefedrin og anvender aceton som oppløsnings-middel. Man får 28,5 g = 78% av addukt I av smeltepunkt 200-204°C One proceeds as described in example 1, however, starting from 21.8 g (0.1 mol) N-formyl-isopropylidene-D,,L-penicillamine and 15.1 g (0.1 mol) 1-norephedrine and uses acetone as solvent. 28.5 g = 78% of adduct I of melting point 200-204°C is obtained
°S L~ vjl° = +31°. °S L~ vjl° = +31°.
Eksempel 6. Example 6.
Man går frem som omtalt i eksempel 53 anvender imidlertid dioksan som oppløsningsmiddel. Man får 28 g = 75% addukt I og smeltepunkt 195 - 196°C og /"a/^<0> = +30,7°. One proceeds as described in example 53, however, dioxane is used as solvent. You get 28 g = 75% adduct I and melting point 195 - 196°C and /"a/^<0> = +30.7°.
Eksempel 7• Example 7•
Man går frem som omtalt i eksempel 5, anvender imidlertid benzen som oppløsningsmiddel. Man får 33 g = 90% addukt I og smeltepunkt 197-201°C og /Ta7p° <=> 31°. One proceeds as described in example 5, however, benzene is used as solvent. You get 33 g = 90% adduct I and melting point 197-201°C and /Ta7p° <=> 31°.
Eksempel 8. Example 8.
Man går frem som omtalt i eksempel 5, anvender imidlertid tetraklorkarbon som oppløsningsmiddel. Man får 34 g = 93% av addukt One proceeds as described in example 5, but carbon tetrachloride is used as solvent. You get 34 g = 93% of adduct
I av smeltepunkt 200-201°C og / a7^° <=><+>35°. I of melting point 200-201°C and / a7^° <=><+>35°.
Eksempel 9. Example 9.
Det ble gått frem som ifølge eksempel 1, imidlertid gått ut fra 51,4 g (0,2 mol) D,L-3-formyl-2,2-pentametylen-5, 5_dimetyl-tiazolidin-4-karboksylsyre og 30,2 g (0,2 mol) 1-norefedrin. Det utvundne salt av D-3~formyl-2,2-pentametylen-5, 5_dimetyl-tiazolidin-4-karboksylsyre og 1-norefedrin hadde en spesifikk dreining på +26° og et smeltepunkt fra 189 til 191°C. Utbyttet utgjorde 33 g, tilsvarende 81%. The procedure was as in example 1, however starting from 51.4 g (0.2 mol) D,L-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and 30.2 g (0.2 mol) 1-norephedrine. The recovered salt of D-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and 1-norephedrine had a specific rotation of +26° and a melting point of 189 to 191°C. The yield was 33 g, corresponding to 81%.
Eksempel 10. Example 10.
Det ble gått frem som i eksempel 1, imidlertid gått ut fra 51,4 g (0,2 mol).D,L-3-formyl-2,2-pentametylen-5,5_dimetyl-tiazolidin-4-karboksylsyre og. 15,1 g (0,1 mol) 1-norefedrin. Det utvundne salt av D-3~formyl-2,2-pentametylen-5, 5-dimetyl-tiazolidin-4-karboksylsyre og 1-norefedrin hadde en spesifikk dreining på +25° og et smeltepunkt fra 190 til 191°G. Utbyttet utgjorde 31 gj tilsvarende l€ >%. Spaltningen av saltet foregikk som omtalt i eksempel 1. Den herved utvundne D-3-formyl-2,2-pentametylen-5 j 5-dimetyl-tiazolidin-4-karboksylsyre hadde en spesifikk dreining på +62,2° og et smeltepunkt fra 191 til 192°C. Herav ble det ved spaltning som omtalt i eksempel 1 oppnådd 9 g D-penicillamin av smeltepunkt 202 til 205°C og spesifikk dreining på -62,5°. The procedure was as in example 1, however starting from 51.4 g (0.2 mol).D,L-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and. 15.1 g (0.1 mol) 1-norephedrine. The recovered salt of D-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and 1-norephedrine had a specific rotation of +25° and a melting point of 190 to 191°G. The dividend amounted to 31 gj corresponding to l€ >%. The splitting of the salt took place as described in example 1. The D-3-formyl-2,2-pentamethylene-5 j 5-dimethyl-thiazolidine-4-carboxylic acid thus obtained had a specific rotation of +62.2° and a melting point from 191 to 192°C. From this, 9 g of D-penicillamine of melting point 202 to 205°C and specific rotation of -62.5° were obtained by cleavage as described in example 1.
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GB1424432A (en) * | 1972-03-25 | 1976-02-11 | Degussa | Pharmaceutical compositions |
DE2304055C3 (en) * | 1973-01-27 | 1982-04-29 | Degussa Ag, 6000 Frankfurt | Process for the production of D-penicillamine |
DE2362687C3 (en) * | 1973-12-17 | 1982-01-14 | Degussa Ag, 6000 Frankfurt | Process for the preparation of the optical isomers of penicillamine |
US4075219A (en) * | 1977-03-31 | 1978-02-21 | Eli Lilly And Company | Epimerization process |
DE3134042A1 (en) * | 1981-08-28 | 1983-03-10 | Degussa Ag, 6000 Frankfurt | METHOD FOR SEPARATING THE RACEMAT S- (CARBOXYMETHYL) - (R, S) -CYSTEIN (A) |
DE3134106A1 (en) * | 1981-08-28 | 1983-03-17 | Degussa Ag, 6000 Frankfurt | METHOD FOR SEPARATING THE RACEMAT S- (CARBOXYMETHYL) - (R, S) -CYSTEIN (B) |
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0
- BE BE786964D patent/BE786964A/en not_active IP Right Cessation
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1971
- 1971-07-30 DE DE2138122A patent/DE2138122C3/en not_active Expired
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1972
- 1972-05-10 ES ES402609A patent/ES402609A1/en not_active Expired
- 1972-05-16 RO RO7270911A patent/RO70841A/en unknown
- 1972-05-17 FI FI1403/72A patent/FI56527C/en active
- 1972-05-22 ZA ZA723486A patent/ZA723486B/en unknown
- 1972-05-25 DD DD163190A patent/DD98093A5/xx unknown
- 1972-06-06 DK DK280972A patent/DK145780C/en active
- 1972-06-16 NO NO2163/72A patent/NO135903C/no unknown
- 1972-06-20 EG EG269/72A patent/EG10792A/en active
- 1972-06-22 CS CS7200004425A patent/CS183662B2/en unknown
- 1972-06-30 NL NL7209189.A patent/NL165153C/en not_active IP Right Cessation
- 1972-06-30 SU SU1806149A patent/SU501669A3/en active
- 1972-07-07 YU YU1514/72A patent/YU36016B/en unknown
- 1972-07-13 GB GB3272672A patent/GB1394855A/en not_active Expired
- 1972-07-17 CH CH1064972A patent/CH580044A5/xx not_active IP Right Cessation
- 1972-07-20 IE IE1016/72A patent/IE36577B1/en unknown
- 1972-07-21 IL IL39963A patent/IL39963A/en unknown
- 1972-07-27 AT AT647072A patent/AT320607B/en not_active IP Right Cessation
- 1972-07-27 FR FR7227091A patent/FR2148050B1/fr not_active Expired
- 1972-07-27 AR AR243308A patent/AR196077A1/en active
- 1972-07-28 AU AU45107/72A patent/AU465833B2/en not_active Expired
- 1972-07-28 BR BR5067/72A patent/BR7205067D0/en unknown
- 1972-07-28 CA CA148,203A patent/CA979924A/en not_active Expired
- 1972-07-28 IT IT51845/72A patent/IT1059660B/en active
- 1972-07-28 SE SE7209900A patent/SE383739B/en unknown
- 1972-07-31 JP JP7684772A patent/JPS544937B1/ja active Pending
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1973
- 1973-10-03 YU YU2593/73A patent/YU36017B/en unknown
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