FI82251B - Novel process for preparing oestriol-16α, 17β dihemisuccinate - Google Patents

Description

82251

The present invention relates to a selective hydrolysis process for the production of estriol-16a, 17B-dihemisuccinate of the formula «3

OCOCHjCHjCOOH

I I OCOCH.CH.COOH

HO

and 16,17-disalts thereof. The compound is of pharmacological value in the treatment of estrogenic deficiency conditions, climacteric and postmenopausal symptoms.

The preparation of a compound of formula I has been previously described in GB 879 014, according to which estriol, i.e. 1,3,5-estratriene-3B, 16a, 17B triol, is esterified with succinic anhydride in pyridine solution. The reaction product is then a hemiester mixture which, in addition to the desired estriol-16α, 17β-dihemisuccinate, also contains a mono-hemi-succinate. The di-hemisuccinate mixture obtained according to this patent is purified by crystallization several times from a mixture of methanol and water.

According to FI patent publication 62541, the above-mentioned compound of the formula I is selectively prepared as 2 82251 so that the 3-salt of estriol of the formula

ch3 OH

^ jf

MO

wherein M represents an alkali or ammonium ion, is esterified by treatment with succinic anhydride in a pyridine-type solvent or a mixed solvent containing a pyridine-type solvent. After the reaction, the compound can be converted to the 16,17-disalt salt with a base.

However, this method has the disadvantage that it involves an additional step, namely the preparation of the 3-salt.

According to the invention, it has now been found that a compound of formula I can be prepared in good yield and purity so that an estriol of formula

CH OH

RPV

(II) esterified at a temperature of up to 70 ° C with succinic anhydride in a pyridine-type solvent, preferably pyridine, to give the trihemisuccinate of the formula 3 82251 ch3 ^ ^ ococh2ch2cooh

I OCOCH, CH, COOH

XU

HOOCH2CH2COCO 'XU XU

which trihemisuccinate is selectively hydrolyzed with water at a temperature of up to about 60 ° C to give the 16,17-dihemisuccinate of formula I, which is optionally converted to the 16,17-disaltate with a base.

The reaction with succinic anhydride is performed for about 4-5 hours. According to the invention, it has been found that the use of temperatures higher than 70 ° C leads to the formation of undesired by-products, in contrast to GB publication 879,014 mentioned at the beginning, where the esterification is carried out at about 90 ° C. In the reaction with succinic anhydride, a smaller amount of dihemisuccinate is formed in addition to the trihemisuccinate, whereby in a typical reaction the ratio of trihemisuccinate to dihemisuccinate may be about 4: 1.

The hydrolysis of the product from the first reaction step with water is performed at a reasonably elevated temperature, at or near about 60 ° C, with a reaction time of about 1-1.5 hours. According to GB patent 879,014, the hydrolysis temperature has not been considered critical. At a lower temperature, the hydrolysis proceeds, but more slowly. The hydrolysis takes place selectively at the 3-position, with the 16- and 17-position ester groups unreacted.

The compound of formula I obtained is, if desired, converted into the 16,17-disalt salt in the customary manner by treating the compound of formula I obtained with an aqueous solution containing a calculated amount of base, for example two equivalents of sodium bicarbonate or an equivalent amount of sodium carbonate.

The method according to the invention achieves considerable advantages over the methods known from the above-mentioned patent publications.

The process is very simple and yields in good yield pure estriol dihemisuccinate in two reaction steps, without the need to isolate, elute or crystallize the product of the first reaction step. The process uses non-hazardous starting materials and does not require protection of the phenol group in a separate step.

The following example illustrates the invention.

Example

30 l of pyridine and 5.77 kg of estriol are introduced into the reactor. The temperature is raised to 50 ° C and 16.0 kg of succinic anhydride are added. The temperature is raised to 68-72 ° C, where the temperature is stirred for 4-5 hours. After completion of the reaction, 30 L of warm water (60 ° C) is added and stirred for one hour at this temperature. The reaction mixture is cooled to about 20 ° C and 60 l of butyl acetate are added and stirred for half an hour. The butyl acetate layer is washed twice with 20 L of 2M H2SO4 (temperature below 20 ° C) and three times with 60 L of water. The butyl acetate phase is treated with 20.0 g of activated carbon and pressure filtered. The filtrate is weighed and the estriol dihemisuccinate content is determined. Yield 7.0-7.5 kg (72-77% of theory). An aqueous solution of 2 equivalents of NaHC (> 3 (based on estriol dihemisuccinate) is added to the butyl acetate phase. Stir for half an hour, finally in vacuo. The layers are separated. The aqueous phase is taken up in 210 l of acetone and stirred for 1-2 hours.

5 82251

Filter and wash the precipitate with acetone. Dry at room temperature. Yield 8.5-9 / 5 kg. (70-77% of theory) of the disodium salt of estriolide hemuccinate.

The product sintered at about 240eC. The IR spectrum of the product is identical to that of the reference substance.

Claims (2)

1. A process for the preparation of estriol-16a, 176-dihemisuccinate of formula CH, / OCOCH N, esterified at a temperature of not more than 70 ° C with succinic anhydride in a pyridine-type solvent, preferably pyridine, to trihemisuccinate of the formula ch3 / OCOCH2CH2COOH J of at most about 60 ° C to 16a, 176-dihemisuccinate of formula I, which, if desired, is transferred to a 16, 17-disalt with a base. 2. A process according to claim 1, characterized in that the hydrolysis is carried out at a temperature of about 60 ° C, the reaction time being about 1-2 hours. II