CS270783B1 - 2 <6.3 Z-Isoalkylidenedioxy-17Q- (3-methyl) -butyryloxy-7-oxa-B-homo-5-Z-androstan-6-one - Google Patents

Abstract

2,3-Isoalkylidenedioxy-17G-(3'-methyl)-butyryloxy-7-oxa-B-homo-5'6-androstan-6-one of general formula I, in which R1 and R2 together represent a compound of general formula II, in which R1 and R4 independently of each other represent the same or different alkyl group, preferably a group with 1 carbon atom, and a process for the preparation of these compounds, characterized in that 2,6,3'6-isoalkylidenedioxy17G-hydroxy-7-oxa-B-homo-5'C-androstan-6-one of general formula III, in which R1 and R2 represent as above, is reacted with an active derivative of 3-methyl-butyric acid in a suitable solvent under catalysis by a tertiary amine.

Description

The present invention relates to 2,6-isoalkylidenedioxy-170- (3-methyl) -butyryloxy-7-oxa-β-homo-5,4-androstan-6-ones and to a process for their preparation. 2,4'-Isoalkylidenedioxy-170- (3-methyl) -butyryloxy-7-oxa-β-homo-5α-C-androstan-6-ones are useful as intermediates for the preparation of 2',3,3'-dihydroxy-170- - (3'-methyl-butyryloxy-1-oxa-β-homo-S'C-androstan-6-one, which affects plant growth in a manner similar to brassinolide.

In 1979, Grove MD et al .: Nature (London) 281, 216 (1979) .7 The plant hormone brassinolide was isolated, which affects the division of plant cells and their elongation, thus affecting plant growth. The accessibility of brassinolide by insulation from natural material is very difficult because it occurs in very low concentrations. For example, rape pollen / ^- Grove M. 0., et al .: Nature (London) 2B1, 216 (1979) _ / contains 0.1 ppm, chestnut galls / ~ Ikeda, M. et al .: Agr. Biol. Chem. 47, 655 (1983). 7 0.005 ppm, in Chinese cabbage Morishita T. et al .: Phytochemistry 22, 1051 (1983) 7 00.000 003 ppm and the like. The accessibility of brassinolide and its analogue by synthesis is also difficult due to the complexity of the synthetic procedures and the low yields. See, for example, Adam G. et al .: Zeitschrift fur Chemie 27, 41 (1987).

In Czechoslovakian A0 270 776 discloses the preparation Lot 3 <XI-dihydroxy-170 (3'-methyl) _{butyryloxy-7-oxa-B-homo-ros} 5ob_ _anc j -t _n _6_onu that affects the growth of plants in a similar manner as brassinolide, of the compounds of formula I-__

wherein R 1 and R 2 independently of one another denote a suitable hydroxyl protecting group which can be selectively removed from the molecule in addition to the 17β- (3'-methyl) -butyryloxy group. Czechoslovak patent application PV 00658-89 describes a process for the preparation of compounds of general formula I, in which R 1 and R 2 represent, independently of one another, acyl groups.

The present invention relates to novel compounds of the above general formula I, 12 'in which R together with R represents an isoalkylidene group of the general formula II

(II) in which R 1 and R 2 independently of one another denote the same or different alkyl groups having 1 to 4 carbon atoms, which can be used as intermediates for the preparation of 2α, 3α-dihydroxy-17β- (3'-methyl) -butyryloxy -7-oxa-β-homo-5α-androstan-6-one, and a process for the preparation of these compounds.

Compounds of formula I in which R together with R represents the above isoalkylidene group may be prepared by preparing compounds of formula III

(III),

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2 in which R together with R represents an abovementioned isoalkylidene group, are reacted with an active 3-methylbutyric acid derivative, preferably its chloride, in a suitable inert organic solvent, for example carbon tetrachloride, catalyzed by a tertiary amine, for example pyridine, or directly in a suitable tertiary amine in which both reactants are soluble, preferably pyridine.

Of the compounds of formula III in which R together with R represents an isoalkylidene group which are used to prepare the compounds according to the invention, there is a literature in the literature ("Kohout L"). et al .: Coll. Czech. Chem. Commun. 52, 1026 (1987). Only one compound is described - 2 2, 3 <4-isopropylidenedioxy-17β-hydroxy-7-oxa-β-homo-5β-androstan-6-one, i.e. the compound of formula III in which R and R together represent an isopropylidene group. Compounds of formula III in which R together with R represents another isoalkylidene group may be prepared by methods known in the literature, for example according to the above citation (Kohout et al.).

Thus, for example, compounds of the above general formula (III) in which R ¹ together with R ² represents the above-mentioned isoalkylidene group can be prepared, for example, by:

2,3,3, 17D-Trihydroxy-7-oxa-β-homo-5H-androstan-6-one of formula IV

reacted with a ketone of formula V ~

R ⁴ - CO - R ⁵ (V), in which R ⁴ and R 4 are as defined above, preferably in this ketone as solvent, in the presence of an acid such as an organic acid such as p-toluenesulfonic acid or camphorsulfonic acid and the like or inorganic acids such as perchloric acid and the like, wherein water is removed from the reaction mixture, for example, anhydrous copper sulfate.

The invention is illustrated by means of non-limiting examples.

Example 1

Preparation of 2H-isopropylidenedioxy-170- (3'-methyl) -butyryloxy-7-oxa-B-homo-5-androstan-6-one

To a solution of 2,4,6-isopropylidenedioxy-17β-hydroxy-7-oxa-β-homo-5α-androstan-6-one prepared according to the literature: Kohout L. et al .: Coll. Czech. Chem. Commun. 52, 1026 (1987). ~ / (150 mg) in pyridine (5 ml) was added dropwise 250 mg of isovaleryl chloride in pyridine (2.5 ml). The reaction mixture was allowed to stand overnight at room temperature. It is then poured into a mixture of ice and water. The product was extracted with ether, the ether layer was separated, washed with 5% hydrochloric acid, water, 10% aqueous potassium hydrogencarbonate solution, water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 180 mg of an oil are thus obtained, which is purified on a silica gel column (100 g) (which contained 10% of potassium carbonate). Elution with a mixture of petroleum ether with chloroform and ether (2: 1: 1) gave 160 mg of oily 2, 1,3-isopropylidenedioxy-17β- (3'-methyl) -butyryloxy-7-oxaB-homo-5β. / -androstan-6-one. IR spectrum: 1742, 1183 (ester), 1717 sh (lactone), 1209, 1122, 1091, 1071 (lactone, isopropylidenedioxy) cm -1. Nuclear Magnetic Resonance Spectrum: 0.86 s, 3H (H-18), 0.90 s, 3H (H-19), 0.96 d, 6H (protons of methyl ester groups, J = 6 Hz), 1.32 s, 3 H and 1.53 s, 3 H (protons of methyl groups of isopropylidenedioxy), 3.31 m, 1H (H-3G, = 18 Hz), 4.08 d, 2H (H-7a, J = 6 Hz), 4.37 s, 1H (H-30), 4.64 m, 1H (Η-17β, W _1/2 = 18 Hz). For C _Q - H, O, (462.6) calculated: 70.10% C, 9.15% H, found 70.05% C, 9.32% H. Z / 4 Z 6

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Example 2

Preparation of 2α, 3β-isobutylidenedioxy-170-hydroxy-7-oxa-β-homo-5β-4-androstan-6-one

To a solution of 2α, 3H, 17β-trihydroxy-7-oxa-β-homo-5α6-androstan-6-one (compound known from the literature, see for example Kohout L. et al .: Coll. Czech. Chem. Commun. 52, 1026 (1987).) (340 mg) in methyl ethyl ketone (10 ml) was added powdered anhydrous copper sulfate (340 mg). 0.1 ml of 70% perchloric acid is added to the suspension. The reaction mixture was stirred magnetically at room temperature for 60 hours. The reaction mixture is then poured into saturated potassium bicarbonate solution and the product is extracted with ether. The ether phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (15θ g), eluting with a 2: 1 mixture of petroleum ether and ether. 242 mg of 2,3-isobutylidenedioxy-17-hydroxy-7-oxa-β-homo-5-androstan-6-one are obtained. Melting point 123-125 ° C (aqueous acetone). IR spectrum (KBr): 3510 (hydroxyl), 1731, 1320, 1189 (lactone), 1168, 1124, 1076, 1066 (isobutylidentithioxy) cm ^- 1. Nuclear Magnetic Resonance Spectrum: 0.79 s, 3H (H-18), 0.90 s, 3H (H-19), 1.05 t, 3H (CH 2 CH 2 -CH 2 O = 7 Hz), 1.54 s, 3H (CH 2 -C-), 3.30 m, 1H (H-2B, W _1/2 = 16 Hz), 3.67 m, 1H (H-17o4, Ν _{χ / 2} 1 16 Hz), 4, 06 d, 2H (H-7a, 3 = 6 Hz), 5.35 br s, 1H (H-38, W _1/2 = 5 Hz). For C ₂ 3 ^H 36 ° 5 ⁽⁴⁰⁸ > ⁵⁾ calculated: 67.62% C, B, B8% H, found: 67.29% C, 8.81% H.

Example 3

Example 2 1 ', 3'-Isobutylidenedioxy-170- (3'-methyl-butyryloxy-T-oxa-B-hpmo-4-sodium-androstan-6-one)

To 2,4'-4-isobutylidenedioxy-170-hydroxy-7-oxa-β-homo-5,4-androstan-6-one (190 mg), which was prepared according to the previous example 2, in pyridine (5 ml) was a solution of 3-methylbutyric acid (0.2 ml) in pyridine (5 ml) was added. The mixture was allowed to stand at room temperature for 20 hours. The reaction mixture is then poured into a mixture of ice and water. The product is extracted with ether. The ether layer was washed with 5% hydrochloric acid, water, 10% aqueous potassium hydrogencarbonate solution, water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 200 mg of an oil are obtained, which is prepared preparatively on 7 silica gel plates (200 x 200 x 0.7 mm), eluting with a 2: 3 mixture of petroleum ether and ether. Treatment of the fractions containing the lipophilic product gave 178 mg of 3α-isobutylidenedioxy-178- (3'-methyl) -butyryloxy-7-oxa-β-homo-5,4-androstan-6-Qnu. Crystallization from aqueous methanol gave 112 mg of crystals, the mother liquors were evaporated to dryness and recrystallized. An additional 45 mg of product is obtained. The total yield of 20β, 30-isobutylidenedioxy-178- (3-methyl) -butyryloxy-7-oxa-β-homo-50C-androstan-6-one was 157 mg. Melting point 178-179 ° C. IR spectrum (carbon tetrachloride): 1744, 1187 (ester, lactone), 1297, 1261, 1172, 1124, 1072 (isobutylidenedioxy, ester) cm ^-1 . ¹ H NMR Spectrum: 0.84 s, 3H (H-18), 0.89 s, ।3H (H-19), 0.96 d, 6H (protons of 178-ester methyl groups) (3 = 7 Hz) 1.05 t, 3H (C £ j _-CH? -O-, 3 = 7 Hz) Ϊ, 57 s, 3H (C-CH), 3.32 d, 1H (H-28, 3 = 6 Hz, 3 '= 10 Hz), 4-, 08 d, 2H (H-7a, 3 = 6 Hz), 4.38 m, 1H (H-3' *, W. _{/ 0} = 5 Hz), 4.65 m, 1H (H-17 <4, W, J = 17 Hz). For C ₁₁ H 11 D (476.6) calculated: 70.55% C, 9.30% H, found: 70.42% C, 9.28% H.

Claims (4)

OBJECT OF THE INVENTION 1. 2,3'-Isoalkylidenedioxy-17β- (3'-methyl) -butyryloxy-7-oxa-β-homo-5α; -androstan-6-one of formula I CS 270783 81 (ID In which R 1 and R 2 independently of one another denote the same or different alkyl group having 1 to 4 carbon atoms. 1 2 2. A process for the preparation of compounds of general formula-I, in which R 1 and R 2 are as defined in point 1, characterized in that 2S, 5β-isoalkylidenedioxy-17β-hydroxy-7-oxa-B- homo-5,4-androstan-6-one of formula III o Wherein R 1 and R 2, as defined in item 1 above, are reacted with an active 3-: 4-ethylsulfuric acid derivative in a suitable organic solvent under tertiary amine catalysis. 3. A process according to claim 2, characterized in that 3-methylbutyric acid chloride is used as the active 3-methylbutyric acid derivative. 4. A process according to claim 2, characterized in that a tertiary amine, preferably pyridine, is used as the organic solvent.