CH263282A - Process for the preparation of penicillamine esters. - Google Patents
Process for the preparation of penicillamine esters.Info
- Publication number
- CH263282A CH263282A CH263282DA CH263282A CH 263282 A CH263282 A CH 263282A CH 263282D A CH263282D A CH 263282DA CH 263282 A CH263282 A CH 263282A
- Authority
- CH
- Switzerland
- Prior art keywords
- penicillamine
- parts
- esters
- esterification
- preparation
- Prior art date
Links
- 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 class 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 title claims description 10
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 230000032050 esterification Effects 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229960001639 penicillamine Drugs 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- ANCLDHSEMKEXLS-BYPYZUCNSA-N (2s)-2-formamido-3-methyl-3-sulfanylbutanoic acid Chemical compound CC(C)(S)[C@H](C(O)=O)NC=O ANCLDHSEMKEXLS-BYPYZUCNSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CZDHUFYOXKHLME-DFWYDOINSA-N (2s)-2-amino-3-methyl-3-sulfanylbutanoic acid;hydrochloride Chemical compound Cl.CC(C)(S)[C@@H](N)C(O)=O CZDHUFYOXKHLME-DFWYDOINSA-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
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 239000004280 Sodium formate Substances 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 229940072049 amyl acetate Drugs 0.000 description 1
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical class O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- VVNCNSJFMMFHPL-UHFFFAOYSA-N penicillamine Chemical compound CC(C)(S)C(N)C(O)=O VVNCNSJFMMFHPL-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
verfahren zur Herstellung von Penicillaminestern. Vorliegende Erfindung bezieht sieh auf ein neues Verfahren zur Herstellung von Penicillaminestern. Die Penicillaminester sind als wertvolle Substanzen, und zwar als Zwi schenprodukte für die Herstellung von ehenio- therapeutischen Mitteln und insbesondere von antibakteriellen Mitteln, welche strukturell mit dem Penicillin verwandt sind, bekannt.
Es wurde gefunden, dass Penicillaminester der Formel (CH")_C'(sH)-C1II(NH,)-C'OOR worin R einen Kohlenwasserstoffrest bedeu tet, gegenüber den bekannten Verfahren, bei welchen Penicillamin mit.
einem Alkohol der Formel ROII umgesetzt wird, mit besserer Ausbeute erhalten werden können, wenn vor gängig der Veresterung das Penicillamin in sein Pormylderivat übergeführt. wird und die anschliessende Veresterung in Gegenwart eines sauren Veresterungskatalysators derart durchgeführt wird, dass gleichzeitig die For- mylgruppe durch Ih-drolyse abgespalten wird.
In den folgenden Beispielen bedeuten die Teile Gewichtsteile.
<I>Beispiel 2</I> Man löst 30 Teile Penicillaminhydrochlo- rid und 12 Teile trockenes Natriumformiat in 240 Teilen Ameisensäure (88%ig), rührt das Gemisch bei 600 C und gibt 85 Teile Essig säureanhydrid zii. Nach einstündigem Erhit- zen und Rühren versetzt, man mit 80 Teilen Wasser und dampft. die Lösung unter vermin dertem Druck zur Trockne ein.
Die zurück bleibende feste Substanz wird aus siedendem Wasser umkristallisiert.. Es entsteht auf diese Weise c11-a-Formylamino-ss-thiol-ss-metliyl-n- huttersäure (N-Forniyl-dl-penicillaniin) vom Smp. 1580 C.
Eine Lösung von 10 Teilen des so erhal tenen N-Formyl-dl-penicillamins in 100 Teilen einer 9n-Lösiuig von Chlorwasserstoff in ab solutem Methylalkohol wird während 16 Stun den unter Rüekfluss erhitzt, das Lösungsmit tel hierauf unter vermindertem Druck ver dampft und der Rückstand erneut in ähn licher Weise mit weiteren 50 Teilen der alko holischen Cblorwasserstofflösung während 2 Stunden erhitzt. Hiernach wird das Lö sungsmittel abdestilliert und das Produkt auskristallisieren gelassen.
Es wird durch wiederholtes Umkristallisieren aus 5/11,' Was ser enthaltendem, tertiärem Butanol oder aus einem Cemiseh. von absolutem :Methanol. und trockenem Äther gereinigt. Auf diese Weise erhält man das Hydrochlorid des lIet.liyl-(ll- U..amino ss-tliiol-ss-methyl-n-butyi@ats vom Smp. 1900 C.
<I>Beispiel 2:</I> Eine Lösung von 10 Teilen N-Formyl-d-a- amino-ss-thiol-ss-methyl-n-buttersäure (N-For- my 1-d-penieillamin, welches durch Formylie- ren von d-Penicillamin in ähnlicher Weise wie in Beispiel 1 für das Formylieren von dl-Penicillamin beschrieben, erhalten wurde)
in 100 Teilen einer 9n-Lösung von Chlorwas serstoff in absolutem '-vlethylalkohol wird während 16 Stunden unter Rückfluss erhitzt. Das Lösungsmittel wird unter vermindertem Druck abdestilliert und der Rückstand erneut in ähnlicher Weise mit weiteren 50 Teilen einer methylalkoholischen Chlorwasserstoff- lösimg während 2 Stunden erhitzt. Das Lö- sungsmittel wird hernach weggedampft, wor auf das Produkt auskristallisiert.
Durch Um- kristallisieren aus einem Gemisch von absolu tem Methanol und trockenem Äther erhält man das Hydrochlorid des Methyl-d-a- amino-fl-thiol-ss methy 1-n-butyr ats vom Smp. 184 0 C.
Das als Ausgangsmaterial verwendete N Formyl-d-penicillamin (Smp. 1580 C) wird aus dem racemischen N-Formyl-penicillamin durch Umlösen des Brucinsalzes erhalten. Beim Kristallisieren aus Methanol scheidet sich d-Salz zuerst aus.
<I>Beispiel 3:</I> Ein Gemisch von 10 Teilen dl-a-Formyl- amino-fl-thiol-ss-methyl-n-buttersäure (herge stellt gemäss Angaben in Beispiel 1) und 100 Teilen trockenem Benzylalkohol wird gekühlt., hierauf so lange Chlorwasserstoff eingeleitet, bis eilte Gewichtszunahme von 10 Teilen er reicht ist, und hernach während 16 Stunden auf dem Wasserbade erhitzt. Dann versetzt. man mit Äther und extrahiert die Lösung reit Wasser.
Der wässerige Extrakt wird hier auf mit Natriumearbonat basisch gestellt und mit Äther extrahiert. Der ätherische Extrakt wird getrocknet uud trockener Chlorwasser stoff hindurchgeleitet. Der ausgefallene Nie derschlag wird abfiltriert und aus Amylace- tat kristallisiert, wobei man das Hydrochlo- rid des Bellzyl-dl-a-amino-ss'-thiol-fl-methyl-n- butyrats vom Smp. 1640 C erhält.
<I>Beispiel 4:</I> Man verfährt in der gleichen Weise wie in Beispiel 1, jedoch verwendet man zur Ver- esterung äthylalkoholisehen Chlorwasserstoff, Das Produkt wird aus einem Gemisch von tert. Butanol und Äther kristallisiert und be steht aus dem Hydrochlorid des Äthyl-dl-a.- amino-ss-thiol-fl-methy 1-n-butyrats vom Smp. 7 r,50 f!
process for the production of penicillamine esters. The present invention relates to a new process for the preparation of penicillamine esters. The penicillamine esters are known as valuable substances, namely as inter mediate products for the production of ehenio-therapeutic agents and in particular of antibacterial agents which are structurally related to penicillin.
It has been found that penicillamine esters of the formula (CH ") _ C '(sH) -C1II (NH,) - C'OOR in which R means a hydrocarbon radical, compared to the known processes in which penicillamine with.
an alcohol of the formula ROII is reacted, can be obtained with better yield if the penicillamine is converted into its pormyl derivative prior to the esterification. and the subsequent esterification is carried out in the presence of an acidic esterification catalyst in such a way that at the same time the formyl group is split off by hydrolysis.
In the following examples, the parts mean parts by weight.
<I> Example 2 </I> 30 parts of penicillamine hydrochloride and 12 parts of dry sodium formate are dissolved in 240 parts of formic acid (88%), the mixture is stirred at 600 ° C. and 85 parts of acetic anhydride are added. After one hour of heating and stirring, 80 parts of water are added and the mixture is evaporated. the solution to dryness under reduced pressure.
The remaining solid substance is recrystallized from boiling water. In this way, c11-a-formylamino-ss-thiol-ss-methyl-n-butyric acid (N-formyl-dl-penicillaniin) with a melting point of 1580 C.
A solution of 10 parts of the N-formyl-dl-penicillamine obtained in this way in 100 parts of a 9N solution of hydrogen chloride in absolute methyl alcohol is refluxed for 16 hours, the solvent is then evaporated under reduced pressure and the residue heated again in a similar way with another 50 parts of the alcoholic Cblorwasserstofflösung for 2 hours. The solvent is then distilled off and the product is allowed to crystallize out.
It is obtained by repeated recrystallization from 5/11, 'What water containing tertiary butanol or from a Cemiseh. of absolute: methanol. and purified with dry ether. In this way, the hydrochloride of lIet.liyl- (ll- U..amino ss-tliiol-ss-methyl-n-butyi @ ats of melting point 1900 C.
<I> Example 2: </I> A solution of 10 parts of N-formyl-da- amino-ss-thiol-ss-methyl-n-butyric acid (N-For- my 1-d-penieillamine, which is ren of d-penicillamine in a manner similar to that described in Example 1 for the formylation of dl-penicillamine)
in 100 parts of a 9N solution of hydrogen chloride in absolute '-vlethylalkohol is heated under reflux for 16 hours. The solvent is distilled off under reduced pressure and the residue is heated again in a similar manner with a further 50 parts of a methyl alcoholic hydrogen chloride solution for 2 hours. The solvent is then evaporated away, whereupon the product crystallizes out.
Recrystallization from a mixture of absolute methanol and dry ether gives the hydrochloride of methyl-d-a-amino-fl-thiol-ss methy 1-n-butyrate with a melting point of 184 ° C.
The N-formyl-d-penicillamine (melting point 1580 ° C.) used as the starting material is obtained from the racemic N-formyl-penicillamine by dissolving the brucine salt. When crystallizing from methanol, the d-salt separates out first.
<I> Example 3: </I> A mixture of 10 parts of dl-a-formylamino-fl-thiol-ss-methyl-n-butyric acid (produced according to the information in Example 1) and 100 parts of dry benzyl alcohol is cooled ., then passed in hydrogen chloride until a rapid increase in weight of 10 parts is reached, and then heated on the water bath for 16 hours. Then moved. one with ether and the solution extracted with water.
The aqueous extract is made basic with sodium carbonate and extracted with ether. The ethereal extract is dried and dry hydrogen chloride passed through it. The precipitated precipitate is filtered off and crystallized from amylacetate, whereby the hydrochloride of Bellzyl-dl-a-amino-ss'-thiol-fl-methyl-n-butyrate with a melting point of 1640 ° C. is obtained.
<I> Example 4: </I> The procedure is the same as in Example 1, except that ethyl alcoholic hydrogen chloride is used for the esterification. The product is made from a mixture of tert. Butanol and ether crystallize and be available from the hydrochloride of ethyl-dl-a.-amino-ss-thiol-fl-methy 1-n-butyrate of mp.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB263282X | 1945-05-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH263282A true CH263282A (en) | 1949-08-31 |
Family
ID=10241927
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH263282D CH263282A (en) | 1945-05-07 | 1946-09-09 | Process for the preparation of penicillamine esters. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH263282A (en) |
-
1946
- 1946-09-09 CH CH263282D patent/CH263282A/en unknown
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