DD277686A1 - PROCESS FOR PREPARING 21-IMINODERIVATES OF 20-KETOPREGNATE DERIVATIVES - Google Patents

Abstract

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

On,.". HC = NR CH ₂ ONO ₂

CO · CO H ₂ NO

I i

Sf S +

St = substituted 17β-androstane residue;

Substituentenz. B.

Keto groups (C3 and / or C11, C12) which may be partially or fully ketalized or converted into imino derivatives with Type III compounds and / or

CC double bonds IA ¹ and / or Δ ⁴ , Δ ⁶ , Δ ¹⁶ ) and / or

OH 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 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-).

Field of application of the invention

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.

Characteristic of the known state of the art

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.

Object of the invention

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.

Explanation of the essence of the invention

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.

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).

embodiments example 1

a) A'-Reichstein S-17-acetate-21-nitrate (Ha)

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 (high resolution): C ₂₃ H ₂₉ NO ₇ , M ⁺ gef. 431, 1945, ber. 431, 1944.

b) 21-dehydro-A'Reichstein S-17-acetate-21-O-carboxymethyl-oxime la

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).

Example 2

21-dehydro-A'Reichstein S-17-acetate-21-oxime (Ib) and its 3-oxime (Ic)

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 (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)

1. A process for the preparation of 21-imino-20-keto-pregnane derivatives of the general formula I. (see Appendix), characterized in that 21-nitrato-20-keto-pregnane derivatives of the general formula II are reacted with amino compounds of the general formula III. 2. The method according to claim 1, characterized in that compounds of general formula III are used as free bases or as salts. 3. The method according to claim 1, characterized in that per mole Il (21-nitrate) 1-3 equivalents of III are used. 4. The method according to claim 1, characterized in that the reaction takes place in solution. Suitable are mixtures of water, lower alcohols, water-miscible ethers with a tertiary amine. 5. The method according to claim 1, characterized in that the reaction takes place at temperatures between 0 ⁰ C and the boiling point of the solvent mixture, preferably at room temperature.