DE1171914B - Process for the preparation of quaternary ammonium salts of basic corticosteroid-21-esters - Google Patents
Process for the preparation of quaternary ammonium salts of basic corticosteroid-21-estersInfo
- Publication number
- DE1171914B DE1171914B DET21279A DET0021279A DE1171914B DE 1171914 B DE1171914 B DE 1171914B DE T21279 A DET21279 A DE T21279A DE T0021279 A DET0021279 A DE T0021279A DE 1171914 B DE1171914 B DE 1171914B
- Authority
- DE
- Germany
- Prior art keywords
- corticosteroid
- ester
- basic
- general formula
- esters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 5
- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- -1 alkyl radical Chemical class 0.000 claims description 6
- 239000003246 corticosteroid Substances 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 8
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 6
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229920002527 Glycogen Polymers 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 229940096919 glycogen Drugs 0.000 description 5
- 229960003512 nicotinic acid Drugs 0.000 description 5
- 239000011664 nicotinic acid Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 235000001968 nicotinic acid Nutrition 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- BVAYTJBBDODANA-UHFFFAOYSA-N Prednisolon Natural products O=C1C=CC2(C)C3CCC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 BVAYTJBBDODANA-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960000890 hydrocortisone Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 3
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NBEMQPLNBYYUAZ-UHFFFAOYSA-N ethyl acetate;propan-2-one Chemical compound CC(C)=O.CCOC(C)=O NBEMQPLNBYYUAZ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung von quaternären Ammoniumsalzen basischer Corticosteroid-21-ester Die Erfindung betrifft ein Verfahren zur Herstellung von quaternären Ammoniumsalzen basischer Corticosteroid-Ester der allgemeinen Formel I in der R1 und R2 Wasserstoffatome oder zusammen eine Doppelbindung, R3 ein Wasserstoffatom, die Hydroxyl- oder die Methylgruppe, R4 ein Wasserstoff- oder Fluoratom, R5 und R6 Wasserstoffatome oder zusammen mit dem Pyridinring einen Chinolinring, R7 einen niederen Alkylrest mit 1 bis 3 Kohlenstoffatomen, den Allylrest oder einen Corticosteroidrest der allgemeinen Formel in der den Resten R1 bis R4 obige Bedeutung zukommt, X (H,OH) oder Ketosauerstoff, Y eine C-C-Bindung, eine Ketogruppe, - CH2 - oder - S - CH2 - und Z ein Chlor-, Brom- oder Jodatom oder den Tosylrest bedeutet.Process for the production of quaternary ammonium salts of basic corticosteroid-21-esters The invention relates to a process for the production of quaternary ammonium salts of basic corticosteroid esters of the general formula I in which R1 and R2 are hydrogen atoms or a double bond together, R3 is a hydrogen atom, the hydroxyl or methyl group, R4 is a hydrogen or fluorine atom, R5 and R6 are hydrogen atoms or together with the pyridine ring is a quinoline ring, R7 is a lower alkyl radical with 1 to 3 carbon atoms , the allyl radical or a corticosteroid radical of the general formula in which the radicals R1 to R4 have the above meaning, X (H, OH) or keto oxygen, Y a CC bond, a keto group, - CH2 - or - S - CH2 - and Z a chlorine, bromine or iodine atom or the Means tosyl radical.
Erfindungsgemäß werden die neuen Verbindungen erhalten, indem man einen basischen Corticosteroid- 21-ester der allgemeinen Formel II auf an sich bekannte Weise mit einer Verbindung der allgemeinen Formel R7 Z, wobei R1 bis R7, X, Y und Z die eingangs erwähnte Bedeutung besitzen, quaternisiert. Die Umsetzung erfolgt zweckmäßig in Anwesenheit eines inerten Lösungsmittels, beispielsweise in Acetonitril, Essigester, Aceton oder Methanol, und zweckmäßig unter Anwendung molarer Mengen der Ausgangsstoffe bzw. eines geringen Überschusses der Verbindung R7 Z. Die Reaktionstemperatur liegt zwischen 20 und 100"C, vorzugsweise bei der Siedetemperatur des verwendeten Lösungsmittels.According to the invention, the new compounds are obtained by adding a basic corticosteroid 21-ester of the general formula II quaternized in a manner known per se with a compound of the general formula R7 Z, where R1 to R7, X, Y and Z have the meanings mentioned at the beginning. The reaction is expediently carried out in the presence of an inert solvent, for example in acetonitrile, ethyl acetate, acetone or methanol, and expediently using molar amounts of the starting materials or a slight excess of the compound R7 Z. The reaction temperature is between 20 and 100 ° C., preferably at the boiling point of the solvent used.
Die als Ausgangsstoffe verwendeten basischen Corticosteroid-21-ester der Formel II sind bekannt, beispielsweise aus der belgischen Patentschrift 621 453. The basic corticosteroid 21-ester used as starting materials of formula II are known, for example from Belgian patent specification 621 453
Quaternäre Ammoniumsalze basischer Corticosteroid-21-ester sind bisher noch nicht beschrieben, es ist besonders überraschend, daß sich auch Verbindungen, in denen R7 einen Corticosteroidrest bedeutet, ohne weiteres herstellen lassen. Die neuen Verbindungen weisen eine gute antiphlogistische Wirksamkeit auf und sind insbesondere für die Anwendung in der Dermatologie geeignet. Quaternary ammonium salts of basic corticosteroid-21-esters are so far not yet described, it is particularly surprising that there are also compounds in which R7 means a corticosteroid residue can be produced without further ado. the new compounds have good anti-inflammatory activity and are particular suitable for use in dermatology.
Die erfindungsgemäß hergestellten Verbindungen weisen insbesondere eine vielfach stärkere Gesamtwirkung auf den Kohlehydrathaushalt auf als bekannte Verbindungen mit vergleichbarer Konstitution. So wurde das erfindungsgemäß hergestellte N - (l l 'S, l 7'a - dihydroxy-pregn - 4'-en- 3',20'- dion-21'-yl) - [3 -carboxy- (prednisolon - 21") -esterj-pyridiniumbromid (HE 85) mittels des Leberglykogentestes mit den bekannten Verbindungen Hydrocortison-21-nicotinsäureester (HE 18) und Hydrocortison-21-isonicotinsäureester (HE 19) verglichen. Die Prüfung erfolgte an der 24 Stunden hungernden intakten Ratte nach einmaliger intramuskulärer Injektion von jeweils äquimolaren Dosen in Anlehnung an die methodischen Angaben von C. C. Porter und R. H. 5 i 1 b e r (Endocrinology 53, 73 [1953]). The compounds prepared according to the invention have in particular a much stronger overall effect on the carbohydrate balance than known Connections with a comparable constitution. So that was made according to the invention N - (l l 'S, l 7'a - dihydroxy-pregn - 4'-en- 3', 20'-dion-21'-yl) - [3 -carboxy- (Prednisolon - 21 ") -esterj-pyridinium bromide (HE 85) by means of the liver glycogen test with the known compounds hydrocortisone-21-nicotinic acid ester (HE 18) and hydrocortisone-21-isonicotinic acid ester (HE 19) compared. The test was carried out on the intact rat starving for 24 hours after a single intramuscular injection of equimolar doses in each case based on to the methodological information from C. C. Porter and R. H. 5 i 1 b e r (Endocrinology 53, 73 [1953]).
Für die Untersuchungen fanden männliche Ratten in einem Gewicht von durchschnittlich 80 g zu Versuchsbeginn Verwendung. Sämtliche Substanzen wurden als mikrokristalline Suspension in einem Wasser-Alkohol-Gemisch 5: 1 (Vol./Vol.) in einem Volumen von 0,5 ml/100 g Tier appliziert. Gemessen wurde die Differenz zwischen den gemittelten Glykogenwerten der steroidbehandelten Tiere und denen nur mit Lösungsmittel behandelter Kontrolltiere in 24stündigen Abständen nach der einmaligen Steroidgabe. Als Näherungswert für das Wirkungsintegral diente die Summe der an den einzelnen Tagen gefundenen Mittelwerte für die Glykogenvermehrung gegenüber den Kontrollen bis zum Ende der Wirkung.For the investigations found male rats weighing 80 g on average at the start of the experiment. All substances were as a microcrystalline suspension in a water-alcohol mixture 5: 1 (vol./vol.) applied in a volume of 0.5 ml / 100 g animal. The difference was measured between the mean glycogen values of the steroid-treated animals and those only Solvent treated control animals at 24 hour intervals after the single Steroid administration. The sum of the was used as an approximation for the action integral the mean values found for the glycogen increase for the individual days the controls until the end of the effect.
Die Ergebnisse sind in der nachstehenden Tabelle zusammengestellt,
n bedeutet die Zahl der jeweils verwendeten Tiere, s die Streuung.
Beispiel 1 N-Methyl-3-carboxy-(hydrocortison-21')-ester-pyridiniumtosylat 1 g Nicotinsäure-(hydrocortison-21)-ester, gelöst in 40ml Acetonitril, und 3 ml p-Toluolsulfonsäuremethylester, gelöst in 4 ml Methanol, werden zusammengegeben und 63 Stunden bei Rückflußtemperatur gehalten. Während dieser Zeit kristallisierten 0,55 g = 78,60/0 der quartären Verbindung aus. Während der Reaktion wurde nochmal 3 g p-Toluolsulfonsäureester zugegeben. Example 1 N-Methyl-3-carboxy- (hydrocortisone-21 ') -ester-pyridinium tosylate 1 g of nicotinic acid (hydrocortisone-21) ester, dissolved in 40 ml of acetonitrile, and 3 ml Methyl p-toluenesulfonate, dissolved in 4 ml of methanol, is combined and held at reflux temperature for 63 hours. During this time crystallized 0.55 g = 78.60 / 0 of the quaternary compound. During the reaction was again 3 g of p-toluenesulfonic acid ester were added.
F. 3l20C (Zersetzung). Dünnschichtchromatogramm bestätigt das Ergebnis. Umkristallisation aus Acetonitril, dem etwas Methanol zugesetzt ist. F. 3120C (decomposition). Thin-layer chromatogram confirms the result. Recrystallization from acetonitrile to which a little methanol has been added.
Beispiel 2 N-(11'ß,17'α-Dioxy-pregn-4'-en-3'.20'-dion-21 '-yl)-[3-carboxy-(hydrocortison-2 1'1-ester]-pyridiniumbromid 1 g Nicotinsäure-(hydrocortison-21)-ester, gelöst in 60 ml Acetonitril, und 0,92 g 21-Bromhydrocortison, gelöst in 70 ml Methanol, werden 35,5 Stunden bei Rückflußtemperatur gehalten. Im Verlauf der Reaktion kristallisiert die quartäre Verbindung aus. Example 2 N- (11'β, 17'α-Dioxy-pregn-4'-en-3'.20'-dione-21'-yl) - [3-carboxy- (hydrocortisone-2 1'1-ester] pyridinium bromide 1 g of nicotinic acid (hydrocortisone-21) ester, dissolved in 60 ml of acetonitrile, and 0.92 g of 21-bromohydrocortisone, dissolved in 70 ml of methanol Maintained at reflux temperature for 35.5 hours. Crystallized in the course of the reaction the quaternary compound.
Eventuell muß noch einmal eine Menge Acetonitril- Methanol zugegeben und zwecks besserem Auskristallisieren etwas eingeengt werden. Es ergeben sich 1,35 g = 71% der leicht gelben, quartären Verbindung vom Schmelzpunkt 255 bis 256°C. Umkristallisation aus Acetonitril: Methanol.You may need to add a lot of acetonitrile Methanol added and narrowed a little for the purpose of better crystallization. The result is 1.35 g = 71% of the light yellow, quaternary compound with a melting point of 255 to 256 ° C. Recrystallization from acetonitrile: methanol.
Beispiel 3 N-( 1 l 7'a-Dioxy-pregn-4'-en-3',20'-dion-21'-yl)- [4-carboxy-(hydrocortison-2 1 ")-ester]-pyridiniumbromid 0,5 g Isonicotinsäure - (hydrocortison - 21) - ester, 0,46 g 21-Bromhydrocortison, 30 ml Acetonitril und 5 ml Methanol werden zusammengegeben und 38 Stunden am Rückfluß erhitzt, wobei 0,4 g = 41,70/0 Quartärverbindung auskristallisieren. Reinigung durch Waschen mit Aceton; F. 249 bis 250°C. Example 3 N- (1 liter 7'a-Dioxy-pregn-4'-en-3 ', 20'-dion-21'-yl) - [4-carboxy- (hydrocortisone-2 1 ") ester] pyridinium bromide 0.5 g isonicotinic acid (hydrocortisone - 21) ester, 0.46 g of 21-bromohydrocortisone, 30 ml of acetonitrile and 5 ml of methanol are combined and heated under reflux for 38 hours, during which 0.4 g = 41.70 / 0 quaternary compound crystallized out. Cleaning by washing with acetone; M.p. 249 to 250 ° C.
Beispiel 4 N-(l 'S,17'a-Dioxy-pregn-4'-en-3 ',20'-dion-21 '-yl)-3-pyridyl-[essigsäure-(hydrocortison-21 ")-ester]-ium-bromid 0,5 g Pyridyl - 3 - essigsäure - (hydrocortison - 21')-ester, 0,4 g 21-Bromhydrocortison, 30 ml Acetonitril und 5 ml Methanol werden zusammengegeben und 22 Stunden am Rückfluß gekocht und 42 Stunden bei Zimmertemperatur stehengelassen. Hierbei kristallisierten 0,3 g = 320/0 der quartären Verbindung aus. Example 4 N- (l 'S, 17'a-Dioxy-pregn-4'-en-3', 20'-dione-21'-yl) -3-pyridyl- [acetic acid- (hydrocortisone-21 ") -ester] -ium-bromide 0.5 g pyridyl - 3 - acetic acid - (hydrocortisone - 21 ') - ester, 0.4 g of 21-bromohydrocortisone, 30 ml of acetonitrile and 5 ml of methanol are combined and refluxed for 22 hours and allowed to stand at room temperature for 42 hours. Here, 0.3 g = 320/0 of the quaternary compound crystallized out.
F. 255,5°C (Zersetzung). Nachweis von Steroid und Brom positiv.Mp 255.5 ° C (decomposition). Evidence of steroid and bromine positive.
Beispiel 5 N-(1 1'ß, 17'a-Dioxy-pregn4'-en-3',20'-dion-21 '-yl)-4- [S-(a-mercaptoessigsäure)-(hydrocortison-21 ")-ester]-pyridiniumbromid 0,5 g 5 - (4- Pyridyl) - a - thioessigsäure - (hydrocortison-21')-ester, 0,42 g 21-Bromhydrocortison, 25 ml Acetonitril und 5 ml Methanol werden zusammengegeben und am Rückfluß 26 Stunden erhitzt und 90 Stunden bei Zimmertemperatur stehengelassen. Example 5 N- (1 1'ß, 17'a-Dioxy-pregn4'-en-3 ', 20'-dione-21'-yl) -4- [S- (a-mercaptoacetic acid) - (hydrocortisone-21 ") ester] -pyridinium bromide 0.5 g 5 - (4- pyridyl) - a - thioacetic acid - (hydrocortisone-21 ') - ester, 0.42 g of 21-bromohydrocortisone, 25 ml of acetonitrile and 5 ml of methanol are combined and refluxed for 26 hours heated and left to stand at room temperature for 90 hours.
Die gewünschte Quartärverbindung kristallisierte aus.The desired quaternary compound crystallized out.
Das orangerote Produkt kann aus Methanol zu Aceton umgelöst werden; F. 242 bis 244"C.The orange-red product can be redissolved from methanol to acetone; F. 242 to 244 "C.
Beispiel 6 N-(11 Igl ,17'a-Dioxy-pregn-4'-en-3',20'-dion-21 '-yl)-[3-carboxy-(prednisolon-21 ")-ester]-pyridiniumbromid 0,55 g Nicotinsäure-(prednisolon-21)-ester, 0,55 g 21-Bromhydrocortison und 35 ml Äthanol werden zusammengegeben und 40 Stunden am Rückfluß gekocht. Nach Einengen im Vakuum wird die auf dem Tonteller zurückbleibende Substanz aus Methanol zu Aceton 1:1 umkristallisiert; F. 222 bis 223"C (Zersetzung). Example 6 N- (11 Igl, 17'a-Dioxy-pregn-4'-en-3 ', 20'-dione-21'-yl) - [3-carboxy- (prednisolone-21 ") -ester] pyridinium bromide 0.55 g of nicotinic acid (prednisolone-21) ester, 0.55 g of 21-bromohydrocortisone and 35 ml of ethanol are combined and refluxed for 40 hours. To The substance remaining on the clay plate is made of methanol by concentrating in vacuo recrystallized to acetone 1: 1; F. 222 to 223 "C (decomposition).
Beispiel 7 N-(ll Iß, 1 7'a-Dihydroxy-pregna- 1',4'-dien-3 ',20'-dion-21 '-yl)- [3-carboxy-(prednisolon-2 1'3-ester]-pyridiniumbromid 0,5 g Nicotinsäure-(prednisolon-2 1 )-ester, gelöst in 30 ml Acetonitril, und 0,46 g 21-Bromprednisolon, gelöst in 5 ml Methanol, werden zusammengegeben und 20 Stunden am Rückfluß gekocht. Beim Einengen scheidet sich ein Öl ab, das abgetrennt wird. Example 7 N- (ll Iß, 17'a-dihydroxy-pregna-1 ', 4'-diene-3', 20'-dione-21 '-yl) - [3-carboxy- (prednisolone-2 1'3-ester] -pyridinium bromide 0.5 g nicotinic acid- (prednisolone-2 1) ester, dissolved in 30 ml of acetonitrile, and 0.46 g of 21-bromoprednisolone, dissolved in 5 ml of methanol are combined and refluxed for 20 hours. When constricting an oil separates, which is separated.
Nach Zusatz von weiterem Acetonitril und 10stündigem Rückflußkochen ergibt sich wieder ein Öl.After adding more acetonitrile and refluxing for 10 hours there is again an oil.
Vereinigung beider Öle. Nach längerem Stehen und Behandeln mit Aceton, dem etwas Methanol zugesetzt wurde, scheiden sich Kristalle ab; F. 224 bis 226"C (Zersetzung).Union of both oils. After standing for a long time and treatment with acetone, to which a little methanol was added, crystals separate out; F. 224 to 226 "C (Decomposition).
Beispiel 8 N-Allyl-3-carboxy-(hydrocortison-21 ')-ester-pyridiniumbromid 0,5 g Mcotinsäure-(hydrocortison-21)-ester, 10 ml Allylbromid und 40 ml Aceton werden zusammengegeben und 80 Stunden am Rückfluß erhitzt. Der Niederschlag kann nach Abfiltrieren in einem Gemisch Aceton-Essigester umkristallisiert werden; F. 147 bis 149"C. Example 8 N-Allyl-3-carboxy- (hydrocortisone-21 ') -ester-pyridinium bromide 0.5 g of mcotinic acid (hydrocortisone-21) ester, 10 ml of allyl bromide and 40 ml of acetone are used combined and heated under reflux for 80 hours. The precipitate can be filtered off be recrystallized in a mixture of acetone-ethyl acetate; F. 147 to 149 "C.
Beispiel 9 N-(l 1'ß, 17'a-Dihydroxy-pregna-l',4'-dien-3'20'-dion-21 '-yl)-[4-carboxy-(prednisolon-21 ")-ester]-pyridiniumbromid 0,5 g Isonicotinsäure - (prednisolon - 21) - ester, 0,46 g 21-Bromprednisolon und ein Gemisch aus 15 ml Äthanol und 30 ml Essigester werden zusammengegeben und 150 Stunden am Rückfluß gekocht. Das angefallene gelbe Produkt wird in Aceton gelöst und durch Zusatz von Essigester zum Kristallisieren gebracht; F. 239 bis 240"C. Example 9 N- (l 1'ß, 17'a-dihydroxy-pregna-l ', 4'-diene-3'20'-dione-21 '-yl) - [4-carboxy- (prednisolone-21 ") -ester] -pyridinium bromide 0.5 g isonicotinic acid - (Prednisolon - 21) - ester, 0.46 g of 21-bromoprednisolone and a mixture of 15 ml Ethanol and 30 ml of ethyl acetate are combined and refluxed for 150 hours cooked. The resulting yellow product is dissolved in acetone and by adding Ethyl acetate brought to crystallize; F. 239 to 240 "C.
Beispiel 10 N-( 11'ß,1 'ß,17'a-Dihydroxy-pregn-4'-en-3 ' ,20'-di on-21 '-yl)- [4-carboxy-(prednisolon-21 ")-ester]-pyridiniumbromid 0,55 g Isonicotinsäure - (prednisolon - 21) - ester, 0,5 g 21-Bromhydrocortison und ein Gemisch aus 30 ml Acetonitril und 5 ml Methanol werden 35 Stunden am Rückfluß gekocht. Das sich in der Wärme abscheidende gelbe Öl wird beim Erkalten fest und kann aus Methanol-Aceton umkristallisiert werden; F. 233 bis 234"C. Example 10 N- (11'β, 1'β, 17'a-dihydroxy-pregn-4'-en-3 ', 20'-di on-21'-yl) - [4-carboxy- (prednisolone-21 ") -ester] -pyridinium bromide 0.55 g isonicotinic acid - (Prednisolon - 21) - ester, 0.5 g of 21-bromohydrocortisone and a mixture of 30 ml of acetonitrile and 5 ml of methanol are refluxed for 35 hours. That I Yellow oil separating in the heat becomes solid on cooling and can be made from methanol-acetone be recrystallized; F. 233 to 234 "C.
Beispiel 11 N-Methyl-3-carboxy-(hydrocortison-2 1)-ester-pyridiniumjodid 0,5 g Nicotinsäure - (hydrocortison - 21) - ester, 10 ml Methyljodid und 40 ml Aceton werden zusammengegeben und 1 Stunde am Rückfluß gehalten. Der sich abscheidende gelbliche Niederschlag kann aus Alkohol umkristallisiert werden; F. 163 bis 164°C (Zersetzung). Example 11 N-methyl-3-carboxy (hydrocortisone-2 1) ester pyridinium iodide 0.5 g of nicotinic acid (hydrocortisone - 21) ester, 10 ml of methyl iodide and 40 ml of acetone are combined and refluxed for 1 hour. The separating yellowish precipitate can be recrystallized from alcohol; 163 to 164 ° C (Decomposition).
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DET21279A DE1171914B (en) | 1961-12-14 | 1961-12-14 | Process for the preparation of quaternary ammonium salts of basic corticosteroid-21-esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DET21279A DE1171914B (en) | 1961-12-14 | 1961-12-14 | Process for the preparation of quaternary ammonium salts of basic corticosteroid-21-esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1171914B true DE1171914B (en) | 1964-06-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DET21279A Pending DE1171914B (en) | 1961-12-14 | 1961-12-14 | Process for the preparation of quaternary ammonium salts of basic corticosteroid-21-esters |
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| Country | Link |
|---|---|
| DE (1) | DE1171914B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2068426A1 (en) * | 1969-11-01 | 1971-08-27 | Unimed Inc |
-
1961
- 1961-12-14 DE DET21279A patent/DE1171914B/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2068426A1 (en) * | 1969-11-01 | 1971-08-27 | Unimed Inc |
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