FIELD OF THE INVENTION

The present invention concerns a process for the preparation of lanosta-8-ene compounds having lanosta-8-ene-7-one or lanosta-8-ene-7-ol compounds as starting material.

BACKGROUND OF THE INVENTION

Cyclic triterpenes, as lanosta-8-ene compounds, are natural chemical compounds, found in many plants, particularly of the Euphorbiaceae family.

Cyclic terpenes are presently known to be obtained by biosynthesis (Nat Prod Rep, 2007;24(6): 1311-31). The present invention is not related to biosynthesis, as will be seen.

The present invention concerns a two step synthesis of specific cyclic triterpenes, namely lanosta-8-ene compounds, from the corresponding ketone lanosta-8- ene-7-one.

DETAILED DESCRIPTION OF THE INVENTION

The process of the invention concerns the following steps: a. contacting one or more lanosta-8-ene-7-one or lanosta-8-ene-7-ol compounds with substituted benzenesulfohydrazide (BSH), particularly tosyl hydrazide (TSH), b. contacting the product resulting from the prior step with a borohydride reducing agent; both steps in a polar protic solvent.

An adequate polar protic solvent is methanol.

Without excluding any other, the metal of the borohydride reducing agent is particularly one or more of alkaline or alkaline earth atoms, more particularly alkaline, among the alkaline preferably sodium, potassium or lithium. An adequate reducing agent is Na(BH4) - sodium borohydride (sodium tetrahydroborate, RN 16940- 66-2).

Non limitative examples of lanosta-8-ene cyclic triterpenes obtained by the invention are:

- euphol (RN 514-47-6)

- tirucallol (RN 514-46-5)

- lanosterol (RN 79-63-0)

- lanostenol (RN 79-62-9)

- euphorbadienol (RN 566-14-3)

- lanost-8-en-3beta,32-diol (RN 59200-39-4)

- lanosterone (RN 5539-04-8)

Lanosta-8,24-diene-3-ols are adequately obtained through the process of the invention, particularly euphol, with

The starting material to obtain the lanosta-8-ene compounds according to the invention are lanosta-8-ene-7-one or lanosta-8-ene-7-ol compounds, with the formula I below:

Formula I

where:

- Rl is - H, or - OH, or - CHO, or -O-CO-(CH ₂ ) _m where m varies from 1 to 10, or r =O - R2 is - H, or - CH ₃ , or - OH;

- R3 is - CH ₃ , or - CHO, or - COOH, or - C=O, or - C-OH, or -0-C0-(CH ₂ ) _m where m varies from 1 to 10;

- R4 is null, or - CH3, or - CH20H, or - CH2=CH2, or - CH ₂ - (CH ₂ ) _n -0H with n = 0, 1, 2 or 3, or - CH(CH ₃ ) ₂ ;

- R5 is - CH3, or - CH ₂ OH, or - CH2=CH2, or - C(CH ₃ ) ₂ , or - CH(CH ₃ ) ₂ , or =CH ₂ , or

- CH(CH3) ₂ OH

- R6 is - OH, or =0

- B is a single or double bond, depending on what R4 or R5 are. Rl to R6 existing in the starting material, namely lanosta-8-ene-7-one or lanosta-8-ene-7-ol, as well as B, will be substantially kept in the resulting lanosta-8-ene compound.

EXAMPLES

The examples given below are concrete embodiments of the invention, brought to prove the enablement thereof, and is not to be taken as including limitations other than the ones presented in the claims attached.

EXAMPLE 1 - Process to obtain euphol

To obtain euphol, a lanosta-8,24-diene-3-ol according to the process of the invention, the lanosta-8-ene-7-one starting material for this example of the invention is kansenone, a cyclic terpene isolated from the plant Euphorbia kansui, according to J.

Nat. Prod, 2003, 66, 630. Kansenone corresponds to the formula I shown further back, where:

Rl is - OH

R2 is - CH ₃

R3 is - CH3

B is a double bond R4 is - CH3

R5 is - CH3

R6 is =0

The explanations below show the process of the invention: Step 1

Step 2

Description of example 1

In a 100 mL flask, equipped with a reflux condenser, 0.2g (0,454 mmol) kansenone (01) and 0.1 183g (0,635 mmol) tosylhydrazide (TSA) were added to 50 mL of methanol. The mixture was heated to about 65 degrees C under reflux for 3 hours, after what it was cooled to room temperature. 0.34Og (8,98 mmol) sodium borohydride (NaBH4) were then added to the mixture in small portions, along one hour, and the mixture was kept under reflux for about 8 hours. The mixture was then cooled to room temperature and the solvent extracted under reduced pressure.

The residue was dissolved in ethyl acetate, transferred to a separation funnel and washed, in that order, with distilled water, diluted sodium carbonate solution, 0.2 M hydrochloric acid and distilled water. The organic phase was separated, anhydrous magnesium sulfate was added to it, and the solvent was evaporated under reduced pressure.

0.180g residue was eluted in a silica gel column with hexane-ethyl acetate gradient, and 0.102g (53% yield) of a white solid with molecular weight of 426 and melting point 1 14-1 15 ⁰ C was obtained (LC-APCI-MS - liquid chromatography - atmospheric pressure chemical ionization mass spectrometric - determination m/z 426 (M) ⁺ - that data confirm the synthesis of euphol (02).

EXAMPLE 2 - Process to obtain tirucallol

Epi-kansenone was the starting material to obtain tirucallol, an epimer of euphol.

The same conditions of example 1 were utilized, with similar results. With the help of the teachings and examples presented herein, a person skilled in the art is able to reproduce the invention in equivalent ways, using the same functions to obtain similar results, without departing from the scope of the invention defined in the attached claims.