CS206311B1 - Method of making the dialcyphosphorous esters of substituted morfinans - Google Patents

Description

(54) A process for producing dialkylphosphoric esters of substituted morphinans

The invention relates to a process for the preparation of dialkylphosphoric esters of substituted morphinans of the general formula I,

wherein R is C 1 -C 4 alkyl.

The compounds of the formula are novel and are valuable intermediates in the pharmaceutical industry.

The process according to the invention is characterized in that the starting (-) - 4,14 R-dihydroxy-3-methoxy-17-methylmorphinan of the formula II

(II)) reacts with phosphonic acid dialkyl esters of formula III,

RO O \ //

P

OF \

RO H (III)

206,311 wherein R is C 1 -C 4 alkyl, in the presence of an organic base and carbon tetrachloride in the range of -5 to +30 ° C.

The reaction is carried out, for example, by adding an ester of the formula III to a solution of the compound of formula II in a mixture of a tertiary organic base and a carbon tetrachloride at a suitable temperature and processing the reaction after completion of the reaction.

Suitable organic bases are, for example, trimethylamine, triethylamine, N-methylpiperidine, pyridine and others.

In the process according to the invention, a stoichiometric amount, preferably an excess of the ester of formula III, is used for the reaction.

Alternatively, the compounds of formula (I) may also be prepared by adding tetraalkylpyrophosphate to a mixture of a compound of formula (II) and a sodium hydroxide solution. However, this method is less preferred, primarily because it provides lower yields.

The following examples illustrate but do not limit the generality of the process of the invention.

Examples

Example 1

To a stirred solution of (-) - 4,14 R-dihydroxy-3-methoxy-17-methylmorphinan (II) (15.3 g, 50 mmol) in a mixture

11.1 ml (80 mmol) of triethylamine and 100 ml of carbon tetrachloride are added dropwise at 10 ° C at 11 ° C over 11 minutes (11.04 g, 80 mmol) of diethyl phosphonate (III, R = CH ₃ CH ₂ ). The mixture was stirred for 1 h and then allowed to stand at room temperature for 24 h. The precipitated triethylamine hydrochloride is then filtered off with suction, the filtrate is washed with 30 ml of water, 25 ml of 1N sodium hydroxide solution and finally with water to neutrality (ca. 3 x 20 ml). After drying over anhydrous sodium sulfate, the organic phase is evaporated on a rotary evaporator and the residue is filtered through a column of 40 g of silica gel in toluene / chloroform (1: 1). Evaporation of the eluate afforded 19.36 g (88.1%) of diethyl (14 R -hydroxy-3-methoxy-17-methylmorphinan-4-yl) phosphate (I, R = CH ₃ CH ₂ ). The substance melts between 88 and 93 ° C.

Example 2

To a mixture of 3.06 g (10 mmol) of (-) - 4,14 R-dihydroxy-3-methoxy-17-methylmorphinan (II, 1.58 g, 20 mmol) of pyridine and 25 mL of carbon tetrachloride is added under cooling to 5 ° C and stirring for 10 minutes 3.88 g (20 mmol) of dibutyl phosphonate (III, R - CH ₃ CH ₂ CH ₂ CH ₂ ). The mixture was stirred under cooling for a further 30 minutes and then allowed to warm to room temperature. After two days of standing, the reaction mixture is washed with 2 x 20 ml of water, 20 ml of 0.5 N potassium hydroxide and 3 x 15 ml of water. The dried organic phase was evaporated in a water pump vacuum. 3.83 g of a thick oil are obtained, which corresponds to 77.4% of the theoretical yield of dibutyl (14 R -hydroxy-3-methoxy-17-methylmorphinan-4-yl) phosphate (I, R = CH ₃ CH ₂ CH ₂ CH ₂ ).

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of dialkylphosphoric esters of substituted morphinans of the general formula I, in which R represents an alkyl of 1 to 4 carbon atoms, characterized in that (-) -4,14 / β-dihydroxy-3-methoxy-17-methylmorphinan of the formula II OH> N — CH ₃ '(II) reacts with phosphonic acid dialkyl esters of formula III, RO O \ // P 206,311 (III) R H in which R is as defined above, in carbon tetrachloride in the presence of a tertiary organic base in the temperature range of -5 to + 30 ° C.