DE1228269B - Process for the preparation of griseofulvin derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 q - 24

Number: 1228 269

File number: G 31589IV b / 12 q

Filing date: February 13, 1961

Opening day: November 10, 1966

The invention relates to a process for the preparation of griseofulvin derivatives of the general formula

OR ₃

R ₂ O

in which Ri and R2 are alkyl groups and R3 is an alkyl or represent an alkenyl group.

According to the invention, the compounds of the formula given above are prepared by that one is a compound of the general formula

RiO 0

OR ₃

R ₂ O

CH ₃

in which Ri, R2 and R _{3 have} the meaning given above, reduced with alkali metal or alkaline earth metal borohydrides.

From the Journal of the Chemical Society (London), 1958, p. 4558, it is known to reduce a griseofulvin compound which contains a keto group in the 4'-position to the corresponding alcohol by means of sodium borohydride. However, the known grisefulvin contains only one reducible keto group, while the starting materials to be used in the present process contain two keto groups. Another difference is that the keto group in the 4 'position in the latter is conjugated with a double bond, whereas this is the case with the known starting materials. It is also known that sodium borohydride in particular has a selective reduction effect insofar as various other groups still present in the molecule and also spaced double bonds such as the starting materials to be used in the present case are not attacked during the reduction of keto groups (cf. for example Wagner-Zook, "Synthetic Organic Chemistry" [1953], p. 149, last paragraph), but it is surprising, and it was also not foreseeable that in the processes for the production of
Griseofulvin derivatives

Applicant:

Glaxo Group Limited,

Greenford, Middlesex (Great Britain)

Representative:

Dr. F. Zumstein, Dr. E. Assmann

and Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Named as inventor:

Jack Lassman, Ilford, Essex (UK)

Claimed priority:
Great Britain dated February 12, 1960 (5178),
dated February 3, 1961

Spirocyclic diketones to be reduced only the keto group in the 4'-position is reduced.

However, this selective reduction is of essential importance, namely during the reduction of the keto group in the spirane ring, a complete and permanent loss of antifungal activity occurs, while the compounds prepared by the process according to the invention · a strong Have activity.

The process according to the invention is expediently carried out in the presence of an inert solvent. The reaction may be carried out at temperatures of 0 to 100 ⁰ C.

Suitable borohydrides to be used are, for example, sodium borohydride, potassium borohydride and Calcium borohydride.

The process product is separated off from the reaction medium in the usual way, z. B., when working in an aqueous medium, by adding an aqueous acid, dilution with water, subsequent separation of the precipitated material and recrystallization of the same, z. B. from benzene.

The products of the process have a biological activity in vivo which is that of the corresponding ones 4'-oxo compounds, but they generally have a low antifungal effect in vitro. However, the process products have

609 710/309

the advantage of greater water solubility than the corresponding 4'-keto compounds, which facilitates the preparation of various pharmaceutical dosage forms, and they are well absorbed due to their solubility. Of particular interest is 7-chloro-4'-hydroxy-6'-methyl-4,6,2 ^/ -trimethoxydgris-2'-en-3-one, which in vivo essentially has the antifungal activity of griseofulvin itself, however, it is far more soluble in water.

Furthermore, the process products can be used for the production of analogous compounds of griseofulvin be used.

The following examples explain the process according to the invention.

example 1

7-chloro-4'-hydroxy-6'-methyl-4,6,2'-trimethoxygris-2'-en-3-one

7.06 g of griseofulvin (0.02 mol) were dissolved in 180 ecm of dioxane and diluted with 45 ecm of water. A solution of 2.16 g of potassium borohydride (0.04 mol; 2 equivalents) in 15 ml of water was then added dropwise with stirring to the dioxane solution, which was then kept at room temperature for 3 hours with occasional shaking. The excess borohydride was then decomposed with dilute acetic acid (strong effervescence) and the whole was poured into 3 l of water with stirring. The mixture was then left to stand at 0 ° C. overnight, the precipitate which had separated out was collected, washed with water and dried over phosphorus pentoxide in vacuo. 4.39 g of crude 7-chloro-4'-hydroxy-6'-methyl-4,6,2'-trimethoxygris-2'-en-3-one with a melting point of 124 ° to 128 ° C. (softening point 104 ° C.) were obtained ⁰ C). After three recrystallization from benzene, 2.40 g of the purified compound with a melting point of 152 ° to 155 ° C. were obtained; [a \ 2 * = + 119.2 ° (c = 1 in acetone).

The infrared spectrum showed the presence of a little benzene, a hydroxyl group and a ketone group (1700 cm " ¹ ). The ultraviolet spectrum in ethanol showed some maxima and minima at the following wavelengths: l _ma , _x at 237 ηΐμ (ε = 15,900 ), 288 ηΐμ (ε = 22 700), 322 πΐμ and lmin at 250 πΐμ (ε = 1300).

Example 2

4-n-Butoxy-7-chloro-4'-hydroxy-6,2'-dimethoxy-6'-methylgris-2'-en-3-one

2.0 g of 4-n-butoxy-7-chloro-6,2'-dimethoxy-6'-methylgris-2'-en-3,4'-dione were in 50 ecm dioxane and 10 ecm water with stirring at room temperature dissolved, and then a solution of 1.5 g of potassium borohydride in 10 cc of water was added dropwise added within 30 minutes. The mixture was then stirred for 3 hours and then over Left for the night. The excess borohydride was then added carefully decomposed by acetic acid and poured the mixture into 250 ecm of water. The mixture then became Chilled in a freezer for 30 minutes

precipitated crude 4-n-butoxy-7-chloro-4'-hydroxy-6,2'-dimethoxy-6'-methylgris-2'-en-3-one is filtered off, washed with water and dried in vacuo at 60.degree . Recrystallization from ethanol gave 1.8 g (9O ° / o of theory) of the pure compound, melting at 152-153 ° C (loss of solvent at 110 to 114 ⁰ C); [a] | ° = + 113 ° (c = 1.008 in acetone, microduct).

Example 3

According to Example 1, the 7-chloro-4'-hydroxy-6, 2 '- dimethoxy - 6' - methyl-4-n-propoxygris-2'-en-3-one obtained in quantitative yield. The compound recrystallized from aqueous alcohol containing 5 to 7 percent by weight of water has a melting point of 175 to 177 ° C .; [a] i ° = + 122.5 ° (c = 1.2 in acetone, microtube).

B e i s ρ i e 1 4

According to Example 1, 6-n-butoxy-7-chloro-4,2'-dimethoxy-6'-methylgris-2'-en-3,4'-dione was converted into 6-η-butoxy-7-chloro-4 '- hydroxy - 4,2' - dimethoxy-6'-methylgris-2'-en-3-one obtained in quantitative yield. Recrystallization from aqueous ethanol containing 5 to 7 percent by weight of water gave the compound from a temperature of 158 to 159 ° C, [a] f = + 108 ° (c = 0.915 in acetone), in a yield of 98.2% get the theory.

Claims (1)

Claim: Process for the preparation of griseofulvin derivatives of the general formula RiO O CH ₃ in which Ri and R2 are alkyl groups and R3 is an alkyl or alkenyl group, characterized in that a compound of the general formula R ₂ O CH ₃ in which Ri, R ₂ and R _{3 have} the meaning given above, reduced with alkali metal or alkaline earth metal borohydrides. Considered publications: Journal of the Chemical Society (London), December 1958, p. 4558; Wagner - Zook, Synthetic Organic Chemistry (1953), p. 149, last paragraph.