CZ374292A3 - Novel process for preparing brassinosteroids - Google Patents

Abstract

A method where R means the hydrogen atom, the hydroxyl group, the acyloxy group with 1 to 5 carbon atoms, the alkyl group with a linear or branched chain or the alkyl group, which is substituted by one, two or more hydroxyl groups, acyloxy groups with 1 to 5 carbon atoms or an amide group where the alkyl group means a group with 1 to 12 carbon atoms, consisting of the oxidation of a compound of general formula I by the action of peroxoacid on an inert solvent at a temperature of 0 degrees C to 40 degrees C for 30 minutes to 30 days.<IMAGE>

Description

Aovy zpusoo preparation of brassinosteroids! ~ π> Ob

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Technique area <->; η I. <r r ~ {<π! N

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The present invention relates to a novel process for the preparation of a lactone ring 3 brašsinosteroid from the corresponding 6-keto-derivative.

The prior art technique

In 1979, Grove M. D. et al. (London) 231, 215 ' (1979). The accessibility of brassinoid from natural material is quite difficult as it occurs at low concentrations, e.g. supra or Ikeda M. et al., Agric. 3iol. Chem. 47, 555 (1935), Morishita T. et al., Phytochemistry et al. Also accessible by chemical synthesis. it is considerably difficult due to the complexity of the synthesis procedures and the low yields (for review see, for example, Adam G. et al., Zeitschrift fur Chemie 27, 41 (1937)). Thus, it is desirable to synthesize brassinoid analogs with high efficiencies that are easier to prepare. Furthermore, it is desirable to simplify as much as possible the synthetic preparation of brassinosteroids, or even brassinoid itself.

The last steps in the synthetic preparation of brassinoid,

The 24-β-brassinide (24R-brassinolide), homobrassinolide and other brassinosteroids with a lactone ring 3 is the preparation of this lactone ring. Starting from compounds of the formula I

wherein R can be hydrogen, hydroxyl, amidyl, any alkyl, acyloxy, hydroxyalkyl, dihydroxyalkyl or polyhydroryalkyl group, diol moiety, optionally other hydroxyl or hydroxyl groups in the side chain are protected with suitable protecting groups, such as, for example, acetates or acetonides and the like to form compounds of formula II

wherein R is _; as described above and the protecting group, the compound of formula (II) thus protected and the corresponding formula II are then suitable

2 wherein R, 5 and R are as defined above. Removal of the hydroxyl protecting groups then yields the desired

wherein R is as above. In addition, this last reaction, which is usually carried out in an alkaline medium, also cleaves the lactone ring, which must be re-sealed by a further reaction with an acid.

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SUMMARY OF THE INVENTION

The process according to the invention is characterized in that the compound of the formula IV is used

wherein S is as defined above, prepares the compounds of formula I mmo from

(AND),

According to the process of the invention, the compound of formula I is oxidized by treatment with a peracid, for example, m-chloroperbenzoic acid or trifluoroperacetic acid, preferably trifluoroperacetic acid, at a temperature in the range of about 0 ° C to about 0 ° C. about 40 ° C, preferably at room temperature, for a period of from 30 minutes to about 30 days, preferably for 2 to 240 hours. The desired compound of formula (IV) is thus obtained directly.

The following examples are intended to illustrate the invention in more detail. However, they are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2a, 3 ^and -Dihydroxy-S-homo-7-oxs-5 ^and -ndrostan-6-one

Solid m-chloroperbenzoic acid was added to a solution of 2a, 3α-dihydroxy-5'-indrostan-6-one (100 mg) in dichloromethane (10 mL). The mixture was allowed to stand at room temperature for 7 days. The progress of the reaction can be controlled by thin layer chromatography on silica gel. The reaction mixture was poured into water, the product was extracted with chloroform, the chloroform layer was separated, washed successively with water, 10% potassium bicarbonate water, dried over sodium sulfate and the solvent was distilled off. The residue (100 mg) was purified on 4 plates of silica gel (20 ml). x 20 x 0.7 mm, eluting with 10: 5 chloroform-ether-isopropyl alcohol 1) · 35 mg of a residue was obtained which crystallized from ethanol to give the title compound, mp 185-188 ° C, ^T E NMR spectrum : 0.74 s, 3H (3 x H-13), 0.52 s, 3K (5 x H-15), 2.53 to 3.53 m, and 3.30 to 4.25 m, 4 H (H) -23, Ή-33 and 2 x E-7a) IR spectrum: 1730, 1712 sh,

320, 1188 (lactone), 3,430, 1065, 1,034 (hydroxyls).

For CΟΟ Η (322.4) calculated: 70.77% C, 5.3S% H, found: 70.41% C, 9.11% E,

Example 2

2α, 5α-Dihydroxy-3-homo-7-oxa-5 ^and -3ndrostan-6-one

To a solution of 2a, 5α-dihydroxy-5 ^and -androstan-6-one (100 mg) in dichloromethane is added a solution of trifluoroacetic acid prepared from 0.46 ml of trifluoroacetic anhydride,

0.08 ml of at least 50% hydrogen peroxide and 1.5 liters of dichloromethane. The mixture was allowed to stand at room temperature for 4 hours. The progress of the reaction can be controlled by silica gel thin layer chromatography. The reaction mixture was poured into water, the product was extracted with chloroform, the chloroform layer was separated, washed with water, 10% potassium bicarbonate, water and dried over sodium sulfate. Distilling off the solvent in vacuo gave 104 mg of product, which was purified over a silica gel column (10 g, eluting with 1: 1 chloroform: ether). 62 mg of product were obtained, which was identical in all respects to the compound prepared in Example 1.

Example 3

2R, 3R-Bihydroxy, -3-homo-7-oxs-3-cholesten-6-one If 2a, 5a-dihydroxy-5 ^and -cholestan-6-one were reacted in a similar manner to Example 1, the title compound was obtained. mp 136-133 ° C (aqueous ethanol), λ 3 ° C + 35 ° (c 1.11), ¹ Ξ K 13 spectrum: 0.33 s, 3 H (3 x H-18), 0.85 d , SK (3 x 26-H and 3 x 27-H, J = 5.3 Hz), 0.90 s, 3 H (H-19 x 3), 2.90 to 4.13 m (H-2) , H-3 and H-7a).

Example 4

2u, 3 ^and -Pihydroxy-3-homo-7-oxa-5 ^and -cholestsin-6-one

If Example 2 was followed except that 2a, 5α-dihydroxy-5α-cholestane was used as the starting compound. 6-one to give the title compound which is identical in all respects to the compound prepared according to Example 3 ·

Example 5

2α, ^3a, 170-trihydroxy-7-oxa-B-homo-5K-androstan-3-one

If 2a, 5a, 1773-trihydroxy-5'-androstan-6-one was reacted in a similar manner to Example 1, the title compound was obtained, m.p. 212-215 ° 0 (methanol-petroleum ether),

1α] 2θ ₊ ⁰ ( _c 1.15), ¹ H HP spectrum: 0.36 s, 3 -E (3 x H-18),

0.76 s, 3K (3 x H-19), 3.20 to 4.19 (overlapped multiplets)

5-H, Η-2β, Η-5β, Η-7εα, Η-7εβ ε Η-17 &, ΐδ spectrum (chloroform):

610, 1026 (hydroxyls), 1722, 1322, 1074 (0-CO) cm ^-1 .

- O Example 6

2a, 5a, 173-Trihydroxy-7-α-β-homo-5 ^and -androstsin-6-one

If Example 2 is followed, rather than using 2a, 5 (, 17S-trihydroxy-5α-sndrostan-6-one) as the starting compound, the title compound is obtained which is in all respects identical to the compound prepared according to Example 2. 5.

Example 7

2α,> α, 173-trihydroxy-7-oxe-S-hmo-5 ^c : -n-6-one, 17-bezozoate

If 2a, 5a, 173-trihydroxy-5 ^and -androsten-6-one such as 17-benzoate are reacted in a similar manner to that described in Example 1 above, the title compound is obtained, mp 244-247 ° C (ethanol), + 74 ⁰ (c 1.2). ^X E NI H H spectrum (DL1SO): 0.50 s, Η (x x H-13), 0.75 s, E (5 x H-19), 2.55 to 4.44 complex m, 4 E (Η-2β, E-β, 2 x E-7a), 4.81. broad triplet (J = 8 Hz, E-17a), 7.51 to 7.77 and 7.50 to 3.14 two m, total 5 H (benzoate protons), IR (K3r): 5 510, 5 440 (hydroxyly), 1712, 1285 (benzoeth),

712, 11 ISO and 1141 sh (lactone) cm -1. Mass spectrum: m / z 442 (MH ⁺ ). For ^C 26 ^K 54 ° 6 calculated: 70.56% C,

7.74% 1H, found: 70.68% 0, 7.71% E.

Example 8

2a, 5a, 173-trihydroxy-7-oxa-.beta.-homo-5.beta.-androstan-6-one, 17-benzoate

Proceeding as in Example 2 except that the starting compound used 2u 5 ^tt, 173-trihydroxy-5a-Andre 'tent-6-benzoate JEKO (17?) To give the title compound, which is in all respects identical with the compound obtained in the preceding Example 7 · 9 rříklad (222, 2j2, 24R) -2a, ^3a, 22,23-tetrahydro dr oxy-24-methyl-7-oxa-B-homoJa hundred-chol-6 -one (24-epibrassinolide)

When (222,232,242) -2a, 3a, 22,23-tetrahydroxy is used

24-methyl-5 ^and -cholestan-6-one were reacted in a similar manner _to that described in Example 1 above to give the title compound, mp 255-257 ° C in accordance with the literature, e.g.

?. Ulevi et al., Phytochemistry 27 (5) »1309 (1933).

Example 10 (222232242) -2a, ^3a, 22,23-tetrahydroxy-24-methyl-7-oxa-3-homo5 $ -cholestan-6-one (24-epibrassinolide)

Proceeding as in Example 2 except that the starting compound used for the reaction (222,232,24-2) 2a, I, 22,23-tetrahydroxy-24-methyl-5 ^Ci -cholestan-6-one to give the title compound, which is identical in all respects to the compound prepared in Example 9 ·

Claims (4)

PATENT Id 2 O K ϊ A process for the preparation of a compound of formula (IV) -lid ÁTšrso v V31 in · · · '. and $ n__ 'í Z 6; x 8 1. (IV) wherein R represents a hydrogen atom, a hydroxyl group, an acyloxy group, a straight or branched chain alkyl group or an alkyl group which is substituted with one, two or more hydroxyl groups, acyloxy groups or an amide group, that Compound (I), wherein R is as above, peracids in an inert solvent of up to about 40 ° C for about 0 minutes to oxidize by treatment at 0 ° C for about 30 days. 2. A process according to claim 1, wherein the inert solvent is dichloromethane. 3. A process according to claim 2, wherein the peracid is trifluoroacetic acid. 4. Process according to claim 3, characterized in that the reaction is carried out at room temperature. 5. A process according to claim 4, wherein the reaction is carried out for 4 hours.