SU635868A3 - Method of obtaining morphine derivatives or solts thereof - Google Patents

Description

X - chlorine, bromine, iodine, B inert organic solvent in the presence of a tertiary amine, the resulting compound of the general formula

Sh

IV

R. W

where k, W, Z. have the indicated meanings, epoxidize with perbenzoic acid in an inert organic solvent, the resulting compound is general

) -w

where k, w, /. have the indicated values, are reduced with lithium yumohydride in an inert organic solvent when heated and, if desired, treated with hydrobromic acid with boron tribromide or pyridine hydrochloride to produce compounds of general formula I, where R is hydrogen, g by subsequent oxidation of the target product in one form or as salt .

Acylation of compounds of the general formula H is carried out in methylene chloride, chloroform, dichloroethane, carbon tetrachloride, benzene, toluene, α-ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamidb, dimethylformamide.

In the alkylation of compounds of the general formula C, lower alkanols, for example, methanol, ethanol, H propanol, isopropanol, etc., can also be used as an inert solvent. Such amines, commonly used as an acceptor of protons in alkylation or acylation reactions, use lower trialkylamines, for example, trimethylamine, triethylamine, pyridine,

N-methylpiperidine.

dimethylaniline. Example

one.

shh

.. x "t

Chu

3-Methoxy-A-morphinan. A mixture of 32.7 g (0.1 mol) of 3-methoxyN -carbethoximorphinan in 160 ml of octanol and 28 g of caustic potash boils t

nitrogen atmosphere 45 min. After cooling, the mixture is treated with water and 600 ml of ether. The organic layer is extracted with 300 ml of 2N. HC1 and 2x300 ml of water. The combined aqueous extracts are alkalinized with an aqueous solution of ammonia, the free base is extracted with ether and 2O g of crude product are obtained. The product was converted to oxalate in anhydrous ether. The salt was recrystallized from acetone-methanol to give 12 g (34.8%), m.p. 180-182 ° C.

After recrystallization from methanol-acetone mixture, a product with m.p. 187-189 ° C.

Calculated,%: C, 66.07; H 6.71; N4.06.

C.7

Found,%: C 66.28; H 6.72; PRI me R 2.

ABOUT

(MOH

H-Cyclopropylcarbonyl-3-methoxy-D ® -morphinan.

3, O g (28.7 mmol) of cyclopropylcarboxylic acid chloride was added to a cooled and stirred solution of 6.4 g (25 mmol) of 3-methoxymorphinan and 2.5 g (31.3 mmol) of pyridine in 30 ml of methylene chloride over Oh min After stirring for 10 minutes, the reaction mixture was washed successively with water, 15 ml of 0.2 N-NaOH solution, 10 ml of 1 N-HCl and again with water. After drying over sodium sulfate, the solvent is distilled off, the residue is crystallized from 15 ml of ether, and 7.73 g (95.7%) of product is obtained with a mp. 125128 C. Recrystallization from methanol, mp. to 133-135 C.

Calculated,%: C 77.98; H7.79; N 4.33.

Cr / N. CHYOD.

Found: C 77.86; H 7.87; N 4, ZO.

PR and ME 3.

SNZO

N-Cyclopropylcarbonyl-8,12-epoxy-3-methoxymorphinan. Puffed to a solution of 3.33 g (10.3 mmol): in Example 2 of the compound in 35 ml of CHgCl, 2.31 g of 85% l-chloroperbenzoic acid (11.3 mmol) is added at 0 ° C. The mixture was stirred until all dissolved over the acid, left at room temperature for 6 hours. After the usual treatment, an oil was obtained, which was dissolved in 10 ml of ether and left for 24 hours at 5 ° C, the precipitate was filtered and 2.3 g (66%) with so pl. 134-136. Recrystallization from a mixture of the CHjClg ester gives a product with m.p. 14O – 142 ° C. Calculated: C, 74.31; H 7.42; K 4.13. Napdeno,%: C 74.13; H 7.39; N4,13. EXAMPLE 4 W-Cyclopropylmethyl-14-hydroxy-3-methoxymorphinan. To a stirred suspension of 1.8 g of lithium aluminum hydride in 5O ml of anhydrous tetrahydrofuran, a solution of 6 g (17 mmol of the compound obtained in example 3 in 1O ml of tetrahydrofuran) is added dropwise over 5 minutes, boiled for 1 h, then treated in the usual way. The product is dissolved in petroleum ether (bp 4O-6O s) and filtered through a mixture of celite and coal to obtain 5.73 g of oil; after treatment with anhydrous HCl ether, 6.15 g (95.5%) of hydrochloride is obtained with t mp 223-225 ° C. Recrystallization of methanol from the mixture increases the melting point to 259-6 O C. Calculated: C 67.67; H 8.37; N3.76. and HC 1 1/2 HgO Found%: C 67.7 O; H 8.02; N 3.72. Example 5: 3,14-Dioxy-N-cyclopropylmethyl morphinan. A. A mixture of 4.1 g of 11.7 mmol of hydrochloride, obtained in example 4, and 13.4 g of anhydrous pyridine hydrochloride, heating JT under nitrogen at 187-195 ° C for 1 h. The cooled cm — CH2 is dissolved in 40 ml of water, basified with aqueous M ammonia and extracted with 2x4O ml of ether After drying and distilling off the solvent, 3 g of a semi-solid are obtained, which is dissolved in ether. After treating with charcoal, the product crystallizes and 2.54 g (69.4%) of the free base are obtained with a mp. 15i7-159 C. Chlorgdrate, recrystallized from methanol-acetone, has so pl. 179-181 ° C with commencement of compression at 163 ° C contains 1/2 crystallization methanol molecules. Calculated,%: C, 67.32; H 8.37; N 3.83, 1/2 Found,%: C 67.56; H 8.20; N3,20, B. In a 3 L cooled-acetone three-neck flask cooled with a stirrer, an addition funnel, a solution of 133.1 g (O, 5312 mol) of boron bromide in 25 O ml of dry methylene chloride is poured. Then a solution of 58 g (0.177 mol) of the free base obtained in Example 4 in 1.2 liters of dry methylene chloride is added dropwise under nitrogen atmosphere over 1 hour. After the addition t is completed, the reaction mixture is stirred in the cold for 1 hour then at room temperature for 3 hours. For 1 hour at 7 ° C, the boron complex hardens and mixing is difficult. In this case, the cooling is stopped and the stirring is carried out after the mass has softened. The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is cooled with ice. and gently decompose with 35 O ml of cold water (a rough reaction may occur at the initial stage of decomposition, therefore it is necessary to vigorously mix and effectively cool the reaction mixture while slowly adding water), transfer to a 4 l Erlenmeyer flask and carefully treat with 20 O ml of concentrated ammonium hydroxide solution while stirring and cooling, the layers are separated, the aqueous layer is extracted with 2OO ml of methylene chloride. The combined organic extracts are dried with magnesium sulphite. H is evaporated under vacuum to give an oil in quantitative yield. The oil is dissolved in 25 O ml of acetone, cooled and treated with 17 ml of concentrated hydrochloric KHcnoTiii. After