NO141827B - ROLLER. - Google Patents

Description

Process for the production of enol halides from the pig liver which can be used as starting materials in the production of griseofulvin analogues.

The present invention relates to a new

method for the production of halogenides of the pig liver which can be used

as starting materials in the production of

griseofulvin analogue.

In Norwegian patent no. 105253 is described

a method for the preparation of compounds (which may be designated as enol halides) with the skeletal structures

in which R denotes a halogen atom and R-'

denotes a hydrogen or halogen atom

or an alkyl group or an aralkyl group.

According to this procedure, one transacts

connections with the skeletal structures

(in which R<1> denotes an alkoxy, aralkyl, aryloxy, alkylthio, aralkylthio or arylthio group or a primary, secondary, tertiary or heterocyclic amino group, while R- has the above meanings , but in formula III can only denote halogen when R<1> denotes an amino group) with phosphorus oxyhalides, preferably phosphorus oxychloride, in the presence of an alkali metal or alkaline earth metal halide, whereby the group R<1> is replaced by an oxo group and the originally present oxo group is replaced by R (a halogen atom).

It is seen that in this method compounds corresponding to structure III of the isogriseofulvin series are transferred to enol halides of the griseofulvin series corresponding to structure I, while compounds of the griseofulvin series corresponding to structures I and IV are transferred to enol halides of the isogriseofulvin series with structure II.

It has now been found that substitution of this type takes place when R- in compounds III and IV is hydrogen, an alkyl group or an aralkyl group and likewise when R- is a halogen atom in compounds of structure IV, but that compounds of structure III in which R - is a halogen atom and R<1> is an ether group or thioether group, does not pass from the isogriseofulvin series to the griseofulvin series, which is transferred to enol halides of the structure II.

The characteristic main feature of the method according to the present invention for the production of enol halides of grisanic acids and which corresponds to the skeletal structure II (in which R and R-, which may be the same or different, denote halogen atoms) is consequently that one reacts a compound corresponding to the skeletal structure III (in which R <1> denotes an ether group or thioether group and R- denotes a halogen atom), in the presence of an alkali metal halide or alkaline earth metal halide, preferably lithium chloride, with phosphorus oxyhalides, preferably phosphorus oxychloride.

The alkali metal halide or alkaline earth metal halide used in the method is suitably a magnesium halide or preferably a lithium halide. When chlorination is to be carried out, a chloride of the mentioned metals is preferably used.

Phosphorus oxychloride is used as a halogenating agent when chloride formation is desired. The phosphorus oxychloride has been found to give particularly good results when it is redistilled shortly before use and mixed with a small amount of water, preferably between 1 and 4 per cent.

The substituent R- is preferably a chlorine or bromine atom, and R<1> is preferably an alkoxy group with from 1 to 5 carbon atoms, e.g. a methyl, ethyl, propyl group etc.

The reaction can be carried out in the presence of a solvent such as an aromatic hydrocarbon, e.g. benzene or toluene, a ketone such as acetone, or an ester, e.g. ethyl acetate. The halogenating agent can serve as a reaction medium when it is liquid at the reaction temperature. However, dilution of the reaction components can reduce the reaction rate.

The starting materials may have sugar substituents in the rings, e.g. in the 4-, 6-, 7-, Order-es, such as e.g. acyloxy, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio, aralkylthio, alkyl, aralkyl or aryl groups or halogen atoms.

Thus, e.g. 3'-chloroisogriseofulvin, an example of the use of which is given below, methoxy groups in the 4- and 6-positions, a chlorine atom in the 7-position and a methyl group in the 6'-position.

Grisans, which have an alkoxy group in the 6-position other than a methoxy group, can be prepared from norgriseofulvic acid by ether ringing to convert the 6- and 2'- or 4'-hydroxyl groups into the desired alkoxy group. After selective hydrolysis of the 2'- or 4'-alkoxy group introduced in this way and reetherethering with a further alkylating agent, a grisan with different alkoxy groups in the 6- and 2'- or 4'-positions can be obtained. Grisanes that have a different alkoxy group in the 4-position than a methoxy group can be prepared by reacting a 4-methoxygrisane, such as griseo-fulvin, with anhydrous magnesium iodide, thereby obtaining the corresponding 4-hydroxy-grisane which can then be preferred with a suitable alkylating agent.

In the following, two embodiments of the invention are described as examples.

Example 1.

Preparation of 7,3',4'-trichloro-4,6-dimethoxy-6'-methyl-gris-3'-ene-3,2'-dione.

0.4 ml of water was added to 10 ml of freshly distilled phosphorus oxychloride to which was then added 0.97 g of anhydrous lithium chloride and 0.97 g of 3'-chloroisogriseofulvin. The mixture was heated on a steam bath for 5 hours, after which excess solvent was removed in vacuo and the residue added to water and ethyl acetate. The organic layer was washed with

diluted hydrochloric acid, sodium carbonate solution and water, after which it was dried over magnesium sulphate and evaporated, whereby 0.84 g of solid material was obtained which, when examined in the infrared range of the spectrum, showed

to contain 70 per cent of the desired product and 30 per cent of the starting material. 1.0 g

of this mixture in 5.0 ml of acetic acid which

containing 1.0 ml of 2 N sulfuric acid was heated on a steam bath for 30 minutes. Most of the solvent speech removed in

vacuum and the residue added with ethyl acetate and water. The ethyl acetate layer was washed with sodium carbonate solution and water. By evaporation of the solvent and subsequent crystallization of the residue from a mixture of ethanol and ethyl acetate, the desired enol chloride was obtained in a pure state and with a melting point of 229-231° C. The product was identical to the sample described in Norwegian patent no. 104776 .

Example 2.

Preparation of 3'-bromo-7,4'-dichloro-4,6-dimethoxy-6'-methylgris-3'-ene-3,2'-dione.

0.2 ml of water was added to 5.0 ml of phosphorus oxychloride to which 0.56 g of lithium chloride and 0.56 g of 3'-bromo-7-chloro-4'-ethoxy-

4,6-dimethoxy-6'-methylgris-3'-ene-3,2'-dione. The mixture was heated on a steam bath for 5 hours. When processed thus

as described in example 1 one got a

foam which crystallized on trituration

with methanol. On recrystallization obtained

one the desired enol chloride. of the product

identity was confirmed by comparison

of its spectrum in the infrared region

with this spectrum for an authentic sample

produced by the method that is

described in Norwegian patent no. 104776.

Claims (3)

1. Method for the production of enol halides which can be used as starting materials in the preparation of grisoful wine analogues, and which have the skeletal structure (in which R and R- which may be the same or different, denote halogen atoms), ca characterized by reacting a compound corresponding to the skeletal structure (in which R<1> denotes an ether group or thioether group and R- denotes a halogen atom), in the presence of an alkali metal halide or alkaline earth metal halide, preferably lithium chloride, with phosphorus oxyhalides, preferably phosphorus oxychloride. 2. Method according to claim 1, characterized in that an excess of phosphorus oxychloride is used as reaction medium. 3. Method according to claim 1 or 2, characterized in that phosphorus oxychloride is used which has been distilled shortly before use and then mixed with from 1 to 4 parts by volume. water.