DK145780B - PROCEDURE FOR THE EXTRACTION OF D-PENICILLAMINE - Google Patents
PROCEDURE FOR THE EXTRACTION OF D-PENICILLAMINE Download PDFInfo
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- DK145780B DK145780B DK280972AA DK280972A DK145780B DK 145780 B DK145780 B DK 145780B DK 280972A A DK280972A A DK 280972AA DK 280972 A DK280972 A DK 280972A DK 145780 B DK145780 B DK 145780B
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- DK
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- penicillamine
- formyl
- norephedrine
- adduct
- mole
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- 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
Description
(19) DANMARK(19) DENMARK
|ρ (12) FREMLÆGGELSESSKRIFT <n> 145780 B| ρ (12) PUBLICATION <n> 145780 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Ansøgning nr. 2809/72 (51) lnt.CI.3 C 07 C 149/243 (22) Indleveringsdag 6. Jun. 1972 (24) Løbedag 6. Jun. 1972 (41) Aim. tilgængelig 31 · Jan. 1973 (44) Fremlagt 28. feb. 19^3 (86) International ansøgning nr. ~ (86) International indleveringsdag (85) Videreførelsesdag -(62) Stamansøgning nr. -(21) Application No. 2809/72 (51) lnt.CI.3 C 07 C 149/243 (22) Filing date 6 Jun. 1972 (24) Race day 6 Jun. 1972 (41) Aim. available 31 · Jan 1973 (44) Posted Feb 28 19 ^ 3 (86) International Application No. ~ (86) International Filing Day (85) Continuation Day - (62) Stock Application No. -
(30) Prioritet 30. Jul. 1971, 21 ?81 22, DE(30) Priority 30 Jul. 1971, 21? 81 22, DE
(71) Ansøger DEGUSSA AKTIENGESELLSCHAFT, 6000 Frankfurt 1, DE.(71) Applicant DEGUSSA AKTIENGESELLSCHAFT, 6000 Frankfurt 1, DE.
(72) Opfinder Friedrich Asinger, DE: Karl-Heinz Gluzek, DE: Heribert(72) Inventor Friedrich Asinger, DE: Karl-Heinz Gluzek, DE: Heribert
Offerraanns, DE: Walter von Bebenburg, DE.Offerraanns, DE: Walter von Bebenburg, DE.
(74) Fuldmægtig Internationalt Patent-Bureau.(74) International Patent Bureau.
(54) Fremgangsmåde til udvinding af D-penicillamin.(54) Process for the extraction of D-penicillamine.
Aminosyren D-penicillamin er kendt som aktivt stof i vigtige lægemidler til behandling af morbus Wilson, defektschizophreni,sklerodermi, cystinuri og kronisk aggressiv hepatitis samt til .basisterapi ved primær kronisk polyarthritis. D-Penicil-lamin finder desuden anvendelse som antidot ved tungtmetalintoxikationer.The amino acid D-penicillamine is known as an active substance in important drugs for the treatment of Wilson's morbidity, defect schizophrenia, scleroderma, cystinuria and chronic aggressive hepatitis as well as for basic therapy in primary chronic polyarthritis. D-Penicil lamin also finds use as an antidote for heavy metal intoxicants.
Kun D-penicillamin kan finde terapeutisk anvendelse, fordi den L-isomere er meget toxisk.Only D-penicillamine can find therapeutic use because the L-isomer is highly toxic.
Det er kendt at udvinde D-penicillamin ved hjælp af en kostbar hydrolytisk w proces ud fra penicillin, hvilken i forbindelse med det kostbare udgangsmaterialeIt is known to recover D-penicillamine by a costly hydrolytic process from penicillin, which in connection with the costly starting material
IDID
30 forklarer denne aminosyres høje pris, der forhindrer bred medicinsk anvendelse af D-penicillamin, især som basisterapeutikum ved kontinuerlig behandling af primær J· kronisk polyarthritis. Af denne grund er tilvejebringelse af en totalsynteee for D-penicillamin af særlig betydning.30 explains the high cost of this amino acid, which prevents the broad medical use of D-penicillamine, especially as a basic therapeutic in the continuous treatment of primary J chronic polyarthritis. For this reason, providing a total synthesis for D-penicillamine is of particular importance.
Det er imidlertid også kendt at fremstille D,L-penicillamin syntetisk og □ 2 145780 deraf udvinde D-penicillamin ved racematspaltning. Som optisk aktive baser anvendes her d-pseudoephedrin og 1-ephedrin ("The Chemistry of Penicilline" (1949),However, it is also known to synthesize D, L-penicillamine synthetically and extract thereof D-penicillamine by racemate cleavage. As optically active bases, here is used d-pseudoephedrine and 1-ephedrine ("The Chemistry of Penicilline" (1949),
Princeton University Press, britisk patentskrift nr. 585.413, US-patentskrift nr. 2.450.784 og belgisk patentskrift nr. 738.520).Princeton University Press, British Patent No. 585,413, U.S. Patent No. 2,450,784 and Belgian Patent No. 738,520).
Til racematspaltning må D,L-penicillamin overføres i egnede derivater, dvs. i penicillaminmolekylet må - således som det er almindeligt ved racematspaltning af aminosyrer - indføres beskyttelsesgrupper. Som til racematspaltning egnede derivater kommer f.eks. N-acyleringsprodukter af D,L-penicillamin eller af S~benzyl~D,L-penicillamin samt acyleringsprodukter af omsætningsprodukter mellem D,L-penicillamin og carbonylforbindelser på tale.For racemate cleavage, D, L-penicillamine must be transferred into suitable derivatives, i.e. Protective groups must be introduced into the penicillamine molecule - as is common in amino acid racemate cleavage). As derivatives suitable for racemate cleavage, e.g. N-acylation products of D, L-penicillamine or of S ~ benzyl ~ D, L-penicillamine as well as acylation products of turnover products between D, L-penicillamine and carbonyl compounds in speech.
Disse fremgangsmåder til racematspaltning af D,L-penicillamin er dog kun lidt tilfredsstillende, da der ved omsætningen mellem D,L-pencillaminderivatet og de nævnte spaltningsbaser sker en udfældning af det uønskede salt af L-penidllamin-derivatet og den optisk aktive hjælpebase. Det er imidlertid kendt, at den af reaktionsopløsningen udkrystalliserede antipode principielt har den største renhed (H.D. Jakubke og H. Jeschkeit, "Aminosåuren, Peptide, Proteine", Akademie-Verlag, Berlin, 1969; samt L. F. Fieser og M.Fieser, "Lehrbuch der Organischen Chemie",However, these processes for racemate cleavage of D, L-penicillamine are only slightly satisfactory, since in the reaction between the D, L-pencillamine derivative and said cleavage bases, a precipitation of the undesired salt of the L-penidillamine derivative and the optically active auxiliary base occurs. However, it is known that, in principle, the antipode crystallized from the reaction solution has the greatest purity (HD Jakubke and H. Jeschkeit, "Amino Acid, Peptide, Protein", Akademie-Verlag, Berlin, 1969; as well as LF Fieser and M.Fieser, "Lehrbuch of Organic Chemistry ",
Verlag Chemie, Weinheim, 1957).Verlag Chemie, Weinheim, 1957).
Der har nu vist sig, at det er særligt fordelagtigt til udvinding af D-penicillamin ud fra D,L-penicillamin at anvende 1-norephedrin (phenylpropanolamin) H CH„ I I 3 C,H - C - C - H 65 i | OH NH2It has now been found that it is particularly advantageous for the extraction of D-penicillamine from D, L-penicillamine to use 1-norephedrine (phenylpropanolamine) H CH 2 I 3 C, H - C - C - H 65 in | OH NH2
Opfindelsen angår i overensstemmelse hermed en fremgangsmåde til udvinding af D-penicillamin ud fra D,L-penicillamin, ved hvilken racematet omdannes til en racematisk N-acyl-2,2-disubstitueret-5,5 dimethyl-thiazolidin-4-carboxylsyre, som omsættes med en optisk aktiv base til en saltblanding, hvorfra saltet af D-N-acyl-2,2-disubstitueret-5,5-dimethyl-thiazolidin-4-carboxylsyre isoleres, hvorpå D-penicillamin fremstilles af dette, og fremgangsmåden er kendetegnet ved, at - den anvendte base er 1-norephedrin.The invention accordingly relates to a process for recovering D-penicillamine from D, L-penicillamine, wherein the racemate is converted to a racematic N-acyl-2,2-disubstituted-5.5 dimethyl-thiazolidine-4-carboxylic acid which is reacted with an optically active base to a salt mixture from which the salt of DN-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxylic acid is isolated and D-penicillamine is prepared therefrom, and the process is characterized by: that - the base used is 1-norephedrine.
Racematspaltningen af D,L-penicillamin forløber ved hjælp denne optisk aktive base med meget store udbytter, og D-penicillamin fås med stor renhed, da det ønskede salt af D-syre og L-base er tungest opløseligt og udfældes.The racemate cleavage of D, L-penicillamine proceeds by means of this optically active base with very high yields, and D-penicillamine is obtained with great purity as the desired salt of D-acid and L-base is most soluble and precipitates.
D,L-penicillamin overføres på kendt måde til en N-acyl-2,2-disubstitueret- 5,5-dimethyl-thiazolidin-4-carboxylsyre, fortrinsvis en sådan med den almene formel 145780 3D, L-penicillamine is transferred in a known manner to an N-acyl-2,2-disubstituted-5,5-dimethyl-thiazolidine-4-carboxylic acid, preferably one of the general formula
COOHCOOH
Η - G - N - Ac 11 “rJ Ur1 C Cv nΗ - G - N - Ac 11 “rJ Ur1 C Cv n
0Η3^ V XR0Η3 ^ V XR
·! o hvor R1 og R^ er ens eller forskellige og betyder et hydrogenatom eller en alkyl-gruppe med 1-8 carbonatomer eller en cycloalkyl- eller arylgruppe , og Ac betyder en acylgruppe, især en benzoyl-, tosyl-, nitrophenylsulfenyl-, acetyl- eller en formylgruppe.·! wherein R 1 and R 2 are the same or different and represent a hydrogen atom or an alkyl group of 1-8 carbon atoms or a cycloalkyl or aryl group, and Ac represents an acyl group, in particular a benzoyl, tosyl, nitrophenylsulphenyl, acetyl or a formyl group.
Blandt disse beskyttede forbindelser foretrækkes yderligere de forbindelser, der fås ved omdannelse af D,L-penicillamin til et N-acetyl- eller fortrinsvis N-formylderivat af en 2,2-dialky1-5,5-dimethy1-thiazolidin-4-carboxylsyre. Blandt disse udmærker sig igen N-formyl-2,2,5,5-tetramethyl-thiazolidin-4-carboxylsyre (N-formyl-isopropyliden-D,L-penicillamin) og N-formy1-2,2-pentamethylen-5,5-dime-thyl-thiazdLidin-4-carboxylsyre. Disse thiazolidin-4-carboxylsyrer kan på simpel måde fremstilles ud fra D,L-penicillamin og passende carbonylforbindelser (The Chemistry of Penicilline (1949), Princeton University Press). Omdannelsen til N-acylforbindelser samt forbindelser med beskyttet mercaptogruppe er beskrevet i samme litteratur.Among these protected compounds, the compounds obtained by converting D, L-penicillamine to an N-acetyl or preferably N-formyl derivative of a 2,2-dialkyl-5,5-dimethyl-thiazolidine-4-carboxylic acid are also preferred. Among these, N-formyl-2,2,5,5-tetramethyl-thiazolidine-4-carboxylic acid (N-formyl-isopropylidene-D, L-penicillamine) and N-formyl-2,2-pentamethylene-5 5-dime-thyl-thiazdLidin-4-carboxylic acid. These thiazolidine-4-carboxylic acids can be prepared simply from D, L-penicillamine and appropriate carbonyl compounds (The Chemistry of Penicilline (1949), Princeton University Press). The conversion to N-acyl compounds as well as compounds with protected mercapto group is described in the same literature.
Som opløsningsmiddel ved racematspaltningen kan foruden vand først og fremmest anvendes organiske opløsningsmidler, f.eks. alkoholer, alifatiske carborihy-drider, halogenerede alifatiske carbonhydrider, ethere, ketoner, estere, aromatiske carbonhydrider og andre. Fortrinsvis anvendes benzen, toluen, isopropanol, di-oxan og lavere carboxylsyreestere.As a solvent in the racemate digestion, in addition to water, organic solvents, e.g. alcohols, aliphatic carbohydrates, halogenated aliphatic hydrocarbons, ethers, ketones, esters, aromatic hydrocarbons and others. Preferably, benzene, toluene, isopropanol, dioxane and lower carboxylic acid esters are used.
Ved gennemførelse af fremgangsmåden ifølge opfindelsen kan man hensigtsmæssigt gå således frem, at man på i og for sig kendt måde overfører.D,L-peradl]amin i en racemisk N-acyl-2,2-disubstLtueret-5,5-dimethyl-thiazolidin-4-carboxylsyre· (be -r skyttet D,L-penicillamin) og opløser denne i vand eller fortrinsvis i et organisk opløsningsmiddel eller en opløsningsmiddelblanding, og til denne blanding, eventuelt under opvarmning, sætter 1-nor-ephedrin, eventuelt opløst i et organisk opløsningsmiddel, hvorved der hyppigt straks, men eventuelt først efter længere tids henstand, eventuelt ved lavere temperatur og efter podning udfældes det tungest opløselige salt af D-formen af nævnte thiazolidincarboxylsyre og 1-norephe-drin, mens det diastereoisomere salt, den optisk aktive antipode eller den racemi-ske blanding henholdsvis de racemiske blandinger heraf forbliver i moderluden.In carrying out the process according to the invention, it is convenient to proceed in such a manner that in a known manner, one transfers D thiazolidine-4-carboxylic acid (protected D, L-penicillamine) and dissolves it in water or preferably in an organic solvent or solvent mixture, and to this mixture, optionally under heating, adds 1-nor-ephedrine, optionally dissolved in an organic solvent, whereby immediately, but possibly only after prolonged standing, optionally at lower temperature and after grafting, the heaviest soluble salt of the D form of said thiazolidine carboxylic acid and 1-norephedrine precipitates, while the diastereoisomeric salt, the optically active antipode or the racemic mixture or the racemic mixtures thereof remain in the mother liquor.
Man kan imidlertid også gå omvendt frem og tilsætte opløsningen af 1-nor-ephedrin den ovennævnte racemiske thiazolidincarboxylsyre, der fortrinsvis er opløst i et organisk opløsningsmiddel 4 145780However, it is also possible to reverse and add the solution of 1-nor-ephedrine to the above-mentioned racemic thiazolidine carboxylic acid, which is preferably dissolved in an organic solvent.
Fremgangsmåden ifølge opfindelsen kan med fordel gennemføres under anvendelse af 0,1 til 3 mol, fortrinsvis 0,5 til 1,1 mol L-norephedrin pr. mol racemat.The process of the invention can advantageously be carried out using 0.1 to 3 moles, preferably 0.5 to 1.1 moles of L-norephedrine per mole. mole racemate.
I alle områder udfældes det tungest opløselige salt af D-formen af den nævnte thiazolidincarboxylsyre og 1—norephedrin. Denne udfældning er ved ca. støkiometriske mængder næsten kvantitativ. Ved anvendelse af mindre end 0,5 mol l-norephedrin forbliver i moderluden racemat og optisk antipode, og anvender man pr. mol racemat 0,5 til 1 mol spaltningsbase, så indeholder moderluden foruden optisk aktiv antipode også et diastereomert salt. Tilfører man pr. mol racemat mere end 1 mol optisk aktiv hjælpebase, så indeholder moderluden foruden diastereomert salt også spaltningsbase.In all regions, the heaviest soluble salt of the D form is precipitated by the said thiazolidinedecarboxylic acid and 1-norephedrine. This precipitation is at approx. stoichiometric quantities almost quantitative. When using less than 0.5 mole of l-norephedrine, the mother liquor remains racemate and optical antipode and is used per day. 0.5 mole of racemate 0.5 to 1 mole of cleavage base, the mother liquor in addition to optically active antipode also contains a diastereomeric salt. Do you add per mole of racemate more than 1 mole of optically active auxiliary base, the mother liquor in addition to diastereomeric salt also contains cleavage base.
Det ved omsætningen fremkomne diastereomere salt af D-formen af thiazolidincarboxylsyre og l-norephedrin kan på grund af de meget gunstige opløseligheds-forhold på i og for sig kendt måde, f.eks. ved filtrering, inddampning af moderluden og rensning ved omkrystallisation, udvindes i ren form.The diastereomeric salt of the D-form of thiazolidine carboxylic acid and l-norephedrine produced by the reaction may, because of the very favorable solubility conditions known per se, e.g. by filtration, evaporation of the mother liquor and purification by recrystallization are recovered in pure form.
Saltet kan på i og for sig kendt måde, f.eks. ved behandling med fortyndede mineralsyrer, overføres til et mineralsurt salt af D-penicillamin, hvorfra D-penicillamin ligeledes på i og for sig kendt måde, f.eks. ved behandling med baser, frigøres.The salt can be known per se, e.g. by treatment with dilute mineral acids, is transferred to a mineral acid salt of D-penicillamine, from which D-penicillamine is also known per se, e.g. when treated with bases, is released.
I hvert tilfælde udfældes ved racematspaltningen først det tungest opløselige salt af D-formen af thiazolidincarboxylsyren og l-norephedrin, mens den anden diastereomere forbliver i opløsning. Dette var overraskende, fordi salte af det tilsvarende L-penicillaminderivat og spaltningsbase er tungest opløselig både ved anvendelse af D-pseudoephedrin og 1-ephedrin.In each case, at the racemate cleavage, the heaviest soluble salt of the D-form of the thiazolidine carboxylic acid and l-norephedrine is precipitated first, while the second diastereomer remains in solution. This was surprising because salts of the corresponding L-penicillamine derivative and cleavage base are most soluble both using D-pseudoephedrine and 1-ephedrine.
På analog måde kan af racematspaltningens moderlud udvindes L-penicillamin.By analogy, L-penicillamine can be recovered from the mother liquor of the racemate digestion.
Det viser sig især særligt fordelagtigt, at L-penicillaminderivatet, som eventuelt er udvundet ved mineralsur spaltning af et salt deraf med optisk aktiv spaltningsbase, på i og for sig kendt måde kan racemiseres, hvorved genanvendelse af den terapeutisk ikke anvendelige L-penicillamin er mulig.It is particularly advantageous that the L-penicillamine derivative, optionally recovered by mineral acid digestion of a salt thereof with optically active cleavage base, can be racemized in a manner known per se, thereby reusing the therapeutically inoperable L-penicillamine .
Eksempel 1 I en 50 1 glasreaktionsbeholder forsynet med omrører, tilbagesvaler, dråbetragt, gastilledningsrør og bundudløbsventil opløses 3,26 kg (15 mol) N-formyl-isopropyliden-D,L-penicillamin, opnået ved omsætning mellem 3 kg D,L-penicillamin-hydrochlorid (16 mol) og 2,81¾ acetone (50 mol) og påfølgende formylering med en blanding af myresyre og acetanhydrid under samtidig neutralisation med natriumacetat, i 20 1 eddikeester under opvarmning til 50°C. Til denne opløsning sætter man under omrøring og yderligere opvarmning 3,28 kg (1,05 x 15 mol) l-norephedrin, opløst i 7 1 eddikeester, hvorved der kan iagttages en temperaturstigning på ca. 5°G. Efter . nogle få minutter udfældes addukt (1) af N-formyl-isopropyliden-D-penicillamin og 1A5780 5 1-norephedrin. Under opvarmning og tilbagesvaling omrører man endnu 1/2 time. Efter afkøling frasuger man kraftigt, vasker med ca. 3 liter eddikeester og tørrer filterresten under formindsket tryk ved ca. 50°C. Man får 2,75 kg = 98% addukt (I) med smp. 200-204°C, [a]J° = +33°.Example 1 A 3.26 kg (15 mol) of N-formyl-isopropylidene-D, L-penicillamine, obtained by reacting between 3 kg of D, L-penicillamine, is dissolved in a 50 liter glass reaction vessel equipped with a stirrer, reflux, drop funnel, gas supply pipe and bottom outlet valve. hydrochloride (16 moles) and 2.81¾ acetone (50 moles) and subsequent formylation with a mixture of formic acid and acetanic anhydride while simultaneously neutralizing with sodium acetate, in 20 L of acetic ester while heating to 50 ° C. To this solution is added, while stirring and further heating, 3.28 kg (1.05 x 15 mole) of l-norephedrine, dissolved in 7 L of vinegar ester, whereby a temperature rise of approx. 5 ° G. After . a few minutes, adduct (1) of N-formyl-isopropylidene-D-penicillamine and 1A5780 5 1-norephedrine is precipitated. During heating and reflux stir for another 1/2 hour. After cooling, you vigorously suction, wash with approx. 3 liters of vinegar ester and dries the filter residue under reduced pressure at approx. 50 ° C. 2.75 kg = 98% adduct (I) is obtained with m.p. 200-204 ° C, [α] D = + 33 °.
Fra moderluden får man efter inddampning til tørhed råt addukt (II) af N-formyl-isopropyliden-L-penicillamin og 1-norephedrin, og derudfra det rene addukt med smp. 116°C og [a]^0 - “74,6° ved omkrystallisation i isopropanol.After evaporation to dryness, crude adduct (II) of N-formyl-isopropylidene-L-penicillamine and 1-norephedrine is obtained, and from there the pure adduct with m.p. 116 ° C and [α] 20 ° - 74.6 ° by recrystallization in isopropanol.
2,75 kg addukt (I) tilsættes ved 25°C først 10 1 destilleret vand og så 1 1 koncentreret saltsyre. Efter 1 times omrøring frasuges kraftigt og vaskes med 2 1 destilleret vand, hvorefter resten tørres ved 50°G under formindsket tryk.2.75 kg of adduct (I) is first added at 25 ° C to 10 L of distilled water and then 1 L of concentrated hydrochloric acid. After stirring for 1 hour, vigorously suction and wash with 2 liters of distilled water, and then the residue is dried at 50 ° G under reduced pressure.
Man får 1,49 kg = 92% N-formyl-isopropyliden-D-penicillamin med smp. 183-184°C1.49 kg = 92% N-formyl-isopropylidene-D-penicillamine with m.p. 183-184 ° C
og [oc]D = +53 . Af moderluden fås efter afdampning til tørhed og omkrystallisation med isopropanol 1,19 kg 1-norephedrin.HCl med smp. 172-174°C.and [oc] D = +53. After evaporation to dryness and recrystallization with isopropanol, 1.19 kg of 1-norephedrine is obtained from the mother liquor. 172-174 ° C.
1,49 kg N-formyl-isopropyliden-D-penicillamin sættes til 9,0 1 15%'s saltsyre, der er opvarmet til 70°C. Under fradestillation af frigjort acetone opvarmer man yderligere 2 timer ved samme temperatur. Efter inddampning til tørhed i en 50 1 rotationsfordamper får 1,08 kg råt D-penicillamin.HCl.1.49 kg of N-formyl-isopropylidene-D-penicillamine is added to 9.0 l of 15% hydrochloric acid heated to 70 ° C. During distillation of released acetone, it is heated for an additional 2 hours at the same temperature. After evaporation to dryness in a 50 L rotary evaporator, 1.08 kg of crude D-penicillamine.HCl.
1,08 kg D-penicillamin.HCl opløses i 8,7 1 96%’s alkohol og tilsættes 0,59 kg (5,82 mol) triethylamin, hvorved frit D-penicillamin udfældes. Efter frasugning, vask med 96%'s alkohol og tørring under formindsket tryk ved 50°C får man 0,78 kg D-penicillamin med smp. 212-214°C og [a]^ = “62,8°.1.08 kg of D-penicillamine. HCl is dissolved in 8.7 1 96% alcohol and 0.59 kg (5.82 mole) of triethylamine is added to precipitate free D-penicillamine. After suction, washing with 96% alcohol and drying under reduced pressure at 50 ° C, 0.78 kg of D-penicillamine is obtained with m.p. 212-214 ° C and [a] + = "62.8 °.
Omarbejdning af det rå addukt (II) sker på analog måde som oparbejdningen af addukt (I). Man får 1,3 kg N-formyl-isopropyliden-1-penicillamin med smp. 182-184°C og L«Jd = “53 .The raw adduct (II) is reworked in an analogous manner to the adduct (I) reprocessing. 1.3 kg of N-formyl-isopropylidene-1-penicillamine is obtained with m.p. 182-184 ° C and L + Jd = "53.
1,3 kg N-formyl-isopropyliden-L-penicillamin opløses i 4,5 1 toluen og tilsættes 30 ml eddikesyreanhydrid. Denne blanding opvarmes to timer under tilbagesvaling. Efter afkøling til stuetemperatur udkrystalliserer rent N-formyl-isopropyliden-D,L-penicillamin. Man får 1,25 kg N-formyl-isopropyliden-D,L-penicillamin med smp. 140-142°C og = 0°·Dissolve 1.3 kg of N-formyl-isopropylidene-L-penicillamine in 4.5 l of toluene and add 30 ml of acetic anhydride. This mixture is heated at reflux for two hours. After cooling to room temperature, pure N-formyl isopropylidene-D, L-penicillamine crystallizes. 1.25 kg of N-formyl-isopropylidene-D, L-penicillamine are obtained with m.p. 140-142 ° C and = 0 °
Eksempel 2 I en 1 liter flerhaIset kolbe forsynet med omrører, dråbetragt, gastilledningsrør og tilbagesvaler opløses 43,5 g (0,2 mol) N-formyl-isopropyliden-D,L-penicillamin i 300 ml eddikeester under opvarmning til 50°C. Til denne opløsning sætter man i portioner i løbet af 5 minutter 16,7 g (0,11 mol) 1-norephedrin og opvarmer yderligere 30 minutter under tilbagesvaling. Efter afkøling til stuetemperatur frasuger man kraftigt, vasker med 150 ml eddikeester og tørrer under formindsket tryk ved 50°C. Man får 33,9 g = 927. N-formyl-isopropyliden-D-penicillamin-1-norephedrin addukt I med smp. 202-204°G og [oc]^* = +31°. Spaltningen af adduktet 6 145780 . sker som beskrevet i eksempel 1. Man får 10 g D-penicillamin med smp. 212-214°C og [a]J° = -62,7°.Example 2 In a 1 liter multistage flask equipped with stirrer, drop funnel, gas supply tube and reflux, dissolve 43.5 g (0.2 mole) of N-formyl-isopropylidene-D, L-penicillamine in 300 ml of vinegar ester while heating to 50 ° C. To this solution, 16.7 g (0.11 mole) of 1-norephedrine are added in portions over 5 minutes and heated for a further 30 minutes under reflux. After cooling to room temperature, vigorously suction, wash with 150 ml of vinegar ester and dry under reduced pressure at 50 ° C. 33.9 g = 927 are obtained. N-formyl-isopropylidene-D-penicillamine-1-norephedrine adduct I, m.p. 202-204 ° G and [oc] + = + 31 °. The cleavage of the adduct 6 145780. occurs as described in Example 1. 10 g of D-penicillamine are obtained with m.p. 212-214 ° C and [a] J ° = -62.7 °.
Eksempel 3Example 3
Man går frem som beskrevet i eksempel 2, men anvender dog isopropylalkohol som opløsningsmiddel. Man får 33,1 g (90%) addukt, ud fra hvilket der ved spaltning fås 9,7 g D-penicillamin med smp. 211-213°C og [a]^ =-62,7 .Proceed as described in Example 2, but use isopropyl alcohol as the solvent. 33.1 g (90%) of adduct is obtained, from which 9.7 g of D-penicillamine is obtained, with m.p. 211-213 ° C and [α] D = -62.7.
Eksempel 4Example 4
Man går frem som beskrevet i eksempel 2, men anvender dog toluen som opløsningsmiddel. Man får 32 g (87%) addukt I med smp. 201-202°C og [a]^ = -31,8°.Proceed as described in Example 2, but use toluene as the solvent. 32 g (87%) of adduct I are obtained with m.p. 201-202 ° C and [α] D = -31.8 °.
Eksempel 5Example 5
Man går frem som beskrevet i eksempel 1, men anvender dog 21,8 g (0,1 mol) N-formyl-isopropyliden-D,L-penicillamin og 15,1 g (0,1 mol) 1-norephedrin og acetone som opløsningsmiddel. Man får 28,5 g = 78% addukt I med smp. 200-204°C og r “120 ,οι® 0JD = +31 .Proceed as described in Example 1 but use 21.8 g (0.1 mole) of N-formyl-isopropylidene-D, L-penicillamine and 15.1 g (0.1 mole) of 1-norephedrine and acetone as solvent. 28.5 g = 78% adduct I is obtained, m.p. 200-204 ° C and r “120, οι® 0JD = +31.
Eksempel 6Example 6
Man går frem som beskrevet i.eksempel 5, men anvender dog dioxan som opløsningsmiddel. Man får 28 g = 75% addukt I med smp. 195-196 C og [α]^ “ +30,7 .Proceed as described in Example 5 but use dioxane as the solvent. 28 g = 75% adduct I is obtained with m.p. 195-196 C and [α] +. + 30.7.
Eksempel 7Example 7
Man går frem som beskrevet i eksempel 5, men anvender dog benzen som opløsningsmiddel. Man får 33 g = 907. addukt I med smp. 197-201 C og [ot]^ = 31 .Proceed as described in Example 5, but use benzene as the solvent. 33 g = 907. Adduct I is obtained, m.p. 197-201 C and [ot] + = 31.
Eksempel 8Example 8
Man går frem som beskrevet i eksempel 5, men anvender dog carbontetrachlorid 2 0 som opløsningsmiddel. Man får 34 g = 93% addukt I med smp. 200-201 C og [ocj^ = +35°.Proceed as described in Example 5, but use carbon tetrachloride 20 as a solvent. 34 g = 93% adduct I is obtained with m.p. 200-201 C and [α] D = + 35 °.
Eksempel 9Example 9
Man går frem som i eksempel 1, idet man dog går ud fra 51,4 g (0,2 mol) D,L-3-formyl-2,2-pentamethylen-5,5-dimethyl-thiazolidin-4-carboxylsyre og 30,2 g (0,2 mol) 1-norephedrin. Det udvundne salt af D-3-formyl-2,2-pentamethylen-5,5-dimethyl-thiazolidin-4-carboxylsyre og 1-norephedrin har en specifik drehning på +26° og et smeltepunkt fra 189 til 191°C. Udbyttet udgør 33 g, svarende til 81%.Proceed as in Example 1, however, starting from 51.4 g (0.2 mole) of D, L-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and 30.2 g (0.2 mole) of 1-norephedrine. The recovered salt of D-3-formyl-2,2-pentamethylene-5,5-dimethyl-thiazolidine-4-carboxylic acid and 1-norephedrine has a specific rotation of + 26 ° and a melting point of 189 to 191 ° C. The yield is 33 g, corresponding to 81%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2138122 | 1971-07-30 | ||
| DE2138122A DE2138122C3 (en) | 1971-07-30 | 1971-07-30 | Process for obtaining D-penicillamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK145780B true DK145780B (en) | 1983-02-28 |
| DK145780C DK145780C (en) | 1983-08-22 |
Family
ID=5815277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK280972A DK145780C (en) | 1971-07-30 | 1972-06-06 | PROCEDURE FOR THE EXTRACTION OF D-PENICILLAMINE |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS544937B1 (en) |
| AR (1) | AR196077A1 (en) |
| AT (1) | AT320607B (en) |
| AU (1) | AU465833B2 (en) |
| BE (1) | BE786964A (en) |
| BR (1) | BR7205067D0 (en) |
| CA (1) | CA979924A (en) |
| CH (1) | CH580044A5 (en) |
| CS (1) | CS183662B2 (en) |
| DD (1) | DD98093A5 (en) |
| DE (1) | DE2138122C3 (en) |
| DK (1) | DK145780C (en) |
| EG (1) | EG10792A (en) |
| ES (1) | ES402609A1 (en) |
| FI (1) | FI56527C (en) |
| FR (1) | FR2148050B1 (en) |
| GB (1) | GB1394855A (en) |
| IE (1) | IE36577B1 (en) |
| IL (1) | IL39963A (en) |
| IT (1) | IT1059660B (en) |
| NL (1) | NL165153C (en) |
| NO (1) | NO135903C (en) |
| RO (1) | RO70841A (en) |
| SE (1) | SE383739B (en) |
| SU (1) | SU501669A3 (en) |
| YU (2) | YU36016B (en) |
| ZA (1) | ZA723486B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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) |
-
0
- BE BE786964D patent/BE786964A/en not_active IP Right Cessation
-
1971
- 1971-07-30 DE DE2138122A patent/DE2138122C3/en not_active Expired
-
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
-
1973
- 1973-10-03 YU YU2593/73A patent/YU36017B/en unknown
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