DD277686A1 - PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES - Google Patents
PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES Download PDFInfo
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- DD277686A1 DD277686A1 DD32265988A DD32265988A DD277686A1 DD 277686 A1 DD277686 A1 DD 277686A1 DD 32265988 A DD32265988 A DD 32265988A DD 32265988 A DD32265988 A DD 32265988A DD 277686 A1 DD277686 A1 DD 277686A1
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- Prior art keywords
- keto
- general formula
- derivatives
- compounds
- imino
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- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 11
- -1 amino compound Chemical class 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 150000003512 tertiary amines Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 101100037762 Caenorhabditis elegans rnh-2 gene Proteins 0.000 abstract 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 abstract 1
- 239000003637 basic solution Substances 0.000 abstract 1
- 238000003379 elimination reaction Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 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
- 230000004071 biological effect Effects 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- KAKVYHQJJMLQFH-UHFFFAOYSA-N methanol;pyridine;hydrate Chemical compound O.OC.C1=CC=NC=C1 KAKVYHQJJMLQFH-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000002577 pseudohalo group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
Verfahren zur Herstellung von 21-Iminoderivaten von 20-Keto-pregnan-derivaten. Anwendungsgebiet sind die Biotechnologie und pharmazeutische Industrie. Das erfindungsgemaesse Verfahren ist dadurch gekennzeichnet, dass 21-Nitrato-20-keto-pregnan-derivate umgesetzt werden mit 1-3 Equivalenten einer entsprechenden Aminoverbindung RNH2 oder einem Salz davon in schwach basischer Loesung vorzugsweise bei Raumtemperatur. Dabei erfolgt unter a-Eliminierung von HNO2 die Bildung der 21-Imino-20-keto-pregnan-derivate.Process for the preparation of 21-imino derivatives of 20-keto-pregnane derivatives. Application area are the biotechnology and pharmaceutical industry. The process according to the invention is characterized in that 21-nitrato-20-keto-pregnane derivatives are reacted with 1-3 equivalents of a corresponding amino compound RNH 2 or a salt thereof in a weakly basic solution, preferably at room temperature. Under a-elimination of HNO2, the formation of the 21-imino-20-keto-pregnane derivatives takes place.
Description
CO · CO H2N-RCO · CO H 2 NO
I II i
Sf S+Sf S +
St = substituierter 17ß-Androstanyl-rest;St = substituted 17β-androstane residue;
Substituentenz. B.Substituentenz. B.
Keto-gruppen (C3 und/oder C11, C12), die teilweise oder vollständig ketalisiert oder mit Verbindungen des Typs III in Iminoderivate überführt sein können und/oderKeto groups (C3 and / or C11, C12) which may be partially or fully ketalized or converted into imino derivatives with Type III compounds and / or
C-C-DoppelbindungenIA1 und/oder Δ4,Δ6,Δ16) und/oderCC double bonds IA 1 and / or Δ 4 , Δ 6 , Δ 16 ) and / or
OH-Gruppen (C 6 und/oder C11, C12/jeweils α- oder ß/, C17 a, C19, die teilweise oder vollständig verestert (ζ. Β. mit Carbonsäuren /C)-Ci0/, die ggf. substituiert sein können) und/oder verethert (ζ. B. mit Alkyl7C,-C|o/, Aralkyl-/z. B. Benzyl-/ oderTriakylsilyl-resten) und/oder ketalisiert sein können und/oder Alkyl (C1-C4) (C6 und/oder C16 jeweils α-oder β-) und/oderOH groups (C 6 and / or C 11, C 12 / in each case α- or β /, C 17 a, C 19, which are partially or completely esterified (ζ Β mit with carboxylic acids / C) -Ci 0 /, which may be substituted can) and / or etherified (ζ B. with Alkyl7C, -C | o /, aralkyl / eg benzyl and / or tri-alkylsilyl radicals) and / or ketalized and / or alkyl (C 1 -C 4 ) (C6 and / or C16 each α- or β-) and / or
Halogen bzw. Pseudohalogen (C6 und/oder C 16/jeweils α- oder ß-/, C9a. R = Alkyl- (Ci-C10) und/oder Aralkyl-, Aryl-, -OR' /R1 = H, (subst.) Alkyl- wie ζ. B. -CH2COR2, wobei R2 = -OH, -O-Alkyl- oder -NR3RVR3, R4 z. B. H-, (subst.) Alkyl-/, -NR5R6 (R5, R6 = H- und/oder Alkyl-, /subst./ Acyl-, Sulfonyl-, /subst./ Aryl-).Halogen or pseudohalogen (C6 and / or C16 / in each case α- or β- /, C9a, R = alkyl (Ci-C 10 ) and / or aralkyl, aryl, -OR '/ R 1 = H, (Subst.) Alkyl such as B.. B. -CH 2 COR 2 , wherein R 2 = -OH, -O-alkyl or -NR 3 RVR 3 , R 4 for example H, (substituted) alkyl - /, -NR 5 R 6 (R 5 , R 6 = H and / or alkyl, /subst./acyl, sulfonyl, /subst./aryl-).
Die Erfindung betrifft ein Verfahren zur Herstellung von 21-lmino-2ü-keto-pregnan-derivaten der allgemeinen Forme ι (s. Anlage). Anwendungsgebiet der Erfindung ist die Biotechnologie bzw. die pharmazeutische Industrie.The invention relates to a process for the preparation of 21-imino-2-keto-pregnane derivatives of the general formula (see Appendix). Field of application of the invention is biotechnology or the pharmaceutical industry.
Bokannt ist das Boispiol der Umsotzung oinos 17a,21-Dihydroxy-20-keto-steroids nach Oxydation der 21-OH-Gruppe in Anwesenheit von Kupfor-ll-ncetat zum 21 -al-Dorivat mit Hydrazin zum 21 -Hydrazon (B. G. Christensen et al., Chem. and Ind. 1958, 1259). Diosos Vorfahren hat don Nachteil, daß os dio Darstellung des labilen 20-Keto-21-aldehyds erfordert.Bokannt is the Boispiol the Umsotzung oinos 17a, 21-dihydroxy-20-keto-steroid after oxidation of the 21-OH group in the presence of Kupfor-ll-acetate to the 21 -al-dorivat with hydrazine to 21-hydrazone (BG Christensen et al., Chem. and Ind. 1958, 1259). Dioso's ancestors have the disadvantage that os dio requires representation of the labile 20-keto-21-aldehyde.
Die Erfindung hat das Ziol, oin Herstellungsverfahren für Verbindungen der allgemeinen Formel I zu finden, das den υ. g. Mangel nicht aufweist, und neue Verbindungen der allgemeinen Formel I bereitzustellen.The invention has the Ziol, oin manufacturing process for compounds of general formula I to find that the υ. G. Lacking, and to provide novel compounds of general formula I.
Erfindungsgemäß werden Verbindungen der allgemeinen Formel I dadurch hergestellt, daß 21-Nitrate der allgemeinen Formel Il (s. Anlage) mit 1-3 Äquivalenten einer Aminoverbindung der allgemeinen Formel Il (s. Anlage) umgesetzt werden. 21-Nitrate (II) sind aus entsprechenden 21-Hydroxyverbindungen nach an sich bekannten Verfahren (z. B. WP 81106) leicht zugänglich. Die Aminoverbindungen (III) können als solche oder in Form ihrer Salze (z. B. Hydrochloride ο. ä.) eingesetzt werden. Werden Salze eingesetzt, so muß das Reaktionsmedium mindestens 1 Äquivalent einer Base enthalten (tert. Amin, Alkali-, Erdalkalicarbonat oder -hydrogencarbonat). Die Umsetzung erfolgt in Lösung bei Temperaturen zwischen 0°C und dem Siedepunkt des Lösungsmittelgemisches, vorzugsweise bei Raumtemperatur. Als Komponenten des Lösungsmittelgemisches eignen sich Wasser, niedere Alkohole, wasserlösliche Ether, Amine wie Pyridin, Triethylamin. Nach beendeter Umsetzung (z. B. chromatographische Kontrolle) wird das Lösungsmittelgemisch entfernt und das Produkt nach an sich bekannten Verfahren wie Kristallisation, Verteilung, Chromatographie o.a. weiter gereinigt.According to the invention, compounds of the general formula I are prepared by reacting 21-nitrates of the general formula II (see Appendix) with 1-3 equivalents of an amino compound of the general formula II (see Appendix). 21-Nitrates (II) are easily accessible from corresponding 21-hydroxy compounds by processes known per se (eg WP 81106). The amino compounds (III) can be used as such or in the form of their salts (for example hydrochlorides or the like). If salts are used, the reaction medium must contain at least 1 equivalent of a base (tertiary amine, alkali metal, alkaline earth metal carbonate or bicarbonate). The reaction takes place in solution at temperatures between 0 ° C. and the boiling point of the solvent mixture, preferably at room temperature. Suitable components of the solvent mixture are water, lower alcohols, water-soluble ethers, amines such as pyridine, triethylamine. After completion of the reaction (eg chromatographic control), the solvent mixture is removed and the product according to known methods such as crystallization, distribution, chromatography o.a. further cleaned.
Das erfindungsgemäße Verfahren liefert überraschend Verbindungen der Formel I. Die Verbindungen weisen potentielle biologische Aktivität auf und stellen außerdem wertvolle Zwischenprodukte für die Synthese biologisch aktiver Steroide dar oder dienen zur Verknüpfung von Steroiden mit Trägermaterialien oder Proteinen. Die Erfindung wird durch die nachstehenden Beispiele beschrieben, ohne dadurch eingeschränkt zu werden. Dünnschichtchromatographie (DC) erfolgt an DC-Alufolien Kieselgel 60F254 (Merck), Detektion mit UV-Licht (254μητι).The process according to the invention surprisingly provides compounds of the formula I. The compounds have potential biological activity and are also valuable intermediates for the synthesis of biologically active steroids or serve to link steroids with carrier materials or proteins. The invention will be described by the following examples without being limited thereby. Thin-layer chromatography (TLC) is carried out on DC aluminum foils silica gel 60F254 (Merck), detection with UV light (254μητι).
a) A'-Reichstein S-17-acetat-21-nitrat (Ha)a) A'-Reichstein S-17-acetate-21-nitrate (Ha)
300mg Δ'-Reichstein S-17-acetat (IV) werden in 2 ml CH2CI2 gelöst und unter Eiskühlung mit der eisgekühlten Mischung von 0,75ml Acetanhydrid und 0,33 ml HNO3 (abs.) versetzt. Nach 35 Min. wird mit 0,5 ml MeOH versetzt. 10 Min. später werden 20 ml Essigester zugesetzt, und die Mischung wird mit H2O, KHCCVLösung (10%ig), H2O gewaschen, mit Na2SO4 abtrocknet und eingedampft: 285mg Ma (85% d. Th.). DC (CHCI3 + 10% Ethanol), RrWerte: IV 0,52, Ua 0,64, Nitratnachweis (Diphenylamin H2SO4): positiv (dunkelblau)300 mg of Δ'-Reichstein S-17-acetate (IV) are dissolved in 2 ml of CH 2 Cl 2 and, while cooling with ice, the ice-cold mixture of 0.75 ml of acetic anhydride and 0.33 ml of HNO 3 (abs.) Is added. After 35 minutes, 0.5 ml of MeOH are added. Ten minutes later, 20 ml of ethyl acetate are added and the mixture is washed with H 2 O, KHCC solution (10%), H 2 O, dried with Na 2 SO 4 and evaporated: 285 mg of Ma (85% of theory). TLC (CHCl 3 + 10% ethanol), R r values: IV 0.52, Ua 0.64, nitrate detection (diphenylamine H 2 SO 4 ): positive (dark blue)
MS (Hochauflösung): C23H29NO7, M+gef. 431,1945, ber. 431,1944.MS (high resolution): C 23 H 29 NO 7 , M + gef. 431, 1945, ber. 431, 1944.
b) 21-Dehydro-A'Reichstein S-17-acetat-21-O-carboxymethyl-oxim lab) 21-dehydro-A'Reichstein S-17-acetate-21-O-carboxymethyl-oxime la
Il a {aus 200mg IV) wird in 2,4ml Methanol + 0,3 ml Pyridin gelöst, mit der Lösung von 60mg H2N-O-CH2CO2H · V2HCI (III a) in 0,2 ml Wasser versetzt und bei 200C 1 Stunde gerührt. Nach 3d wird im N2-Strom eingedampft und der Rückstand an 20g SiO2 (Serva Si 100,0,03mm) chromatographiert mit CHCI3+ 1 % Ethanol: 212 mg la (85%d. Th.). DC (CHCI3+ 10% Ethanol), R,-Werte: Ha 0,64, la 0,08, IV 0,52, MS (Hochauflösung) des Methylesters von la: C26H33NO7, N* gef. 471,2258, ber. 471,2257. 1H-NMR (CDCI3, δ, ppm): 7,70 (1H, S, H-21), 0,70 (3H, S, H-18), 4,75 (2H, S, O-Carboxymethyl-oxim).Il a {from 200 mg IV) is dissolved in 2.4 ml of methanol + 0.3 ml of pyridine, with the solution of 60mg H 2 NO-CH 2 CO 2 H · V2HCl (III a) in 0.2 ml of water and at 20 0 C stirred for 1 hour. After 3d, the mixture is evaporated in an N 2 stream and the residue is chromatographed on 20 g of SiO 2 (Serva Si 100.0.03 mm) with CHCl 3 + 1% ethanol: 212 mg of La (85% of theory). TLC (CHCl 3 + 10% ethanol), R, values: Ha 0.64, La 0.08, IV 0.52, MS (high resolution) of the methyl ester of Ia: C 26 H 33 NO 7 , N *. 471.2258, about 471.2257. 1 H-NMR (CDCl 3 , δ, ppm): 7.70 (1H, S, H-21), 0.70 (3H, S, H-18), 4.75 (2H, S, O-carboxymethyl oxime).
21-Dehydro-A'Reichstein S-17-acetat-21-oxim (Ib) und sein 3-Oxim (Ic)21-dehydro-A'Reichstein S-17-acetate-21-oxime (Ib) and its 3-oxime (Ic)
200mg Ha werden in 20ml Methanol-Pyridin-Wasser (4:1:1) gelöst und nach Zugabe von 50mg NhI2OH HCI (HIb) 1 Stunde bei 20°C gerührt. Nach einem Tag wird im N2-Strom eingedampft und der Rückstand an SiO2 chromatographiert mit CHCI3 + 3% Ethanol: 142,6mg Ib (77%d. Th.) und 15,4mg Ic (8%d. Th.). DC (CHCI3+ 3% Ethanol, 2 x), RrWerte: Ib0,46, k0,24, Ha 0,61.200 mg of HA are dissolved in 20 ml of methanol-pyridine-water (4: 1: 1) and, after addition of 50 mg of NhI 2 OH HCl (HIb), stirred at 20 ° C. for 1 hour. After one day, the mixture is evaporated in an N 2 stream and the residue is chromatographed on SiO 2 using CHCl 3 + 3% ethanol: 142.6 mg of Ib (77% of theory) and 15.4 mg of Ic (8% of theory). , TLC (CHCl 3 + 3% ethanol, 2x), R r values: Ib 0.46, k 0.24, Ha 0.61.
MS (Hochauflösung)·. Ib = C23H29NO5: M* gef. 399,2050, ber. 399,2046. Ic = C23H30N2O6: M* gef. 414,2164, ber. 414,2155.MS (high resolution) ·. Ib = C 23 H 29 NO 5: M * gef. 399,2050, about 399,2046. Ic = C 23 H 30 N 2 O 6: M * gef. 414,2164, 414,2155.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD32265988A DD277686A1 (en) | 1988-12-03 | 1988-12-03 | PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD32265988A DD277686A1 (en) | 1988-12-03 | 1988-12-03 | PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD277686A1 true DD277686A1 (en) | 1990-04-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD32265988A DD277686A1 (en) | 1988-12-03 | 1988-12-03 | PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES |
Country Status (1)
| Country | Link |
|---|---|
| DD (1) | DD277686A1 (en) |
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1988
- 1988-12-03 DD DD32265988A patent/DD277686A1/en not_active IP Right Cessation
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