SU428600A3 - METHOD OF OBTAINING TERTIARY AMINO ACIDS OR THEIR SALTS - Google Patents

Description

The invention relates to the field of the preparation of physiologically active compounds which can be used in pharmaceutical practice. Using a method known in organic chemistry for obtaining fatty-aromatic acid amides by reacting aryl methyl ketone with sulfur and ammonia or a primary or secondary amine | biological activity. The proposed method for the preparation of tertiary amino acids of the general formula N-Fh-CHgCOOH where Ph is a substituted or unsubstituted phenylene residue; A is lower alkylene, alkenylene, azaalkylene, oxaalkylene, thiaalkllene, and the two existing heteroatoms are separated from each other by at least one carbon atom, or their salts, is that the compound of the general formula. J-Ph-CO-CH. where Ph and A have the indicated meanings, are subjected to interaction with sulfur and ammonia or a primary or secondary amine when heated, preferably at the boiling point of the reaction mass: the resulting thioamide or acid amide is subjected to hydrolysis, followed by separation of the target product in free form Or by transferring it to salt in a known manner. Example 1. A mixture of 8.53 g of 4-piperi: d.O. aceto | fe; no1na, 7.5 g of sulfur, 6 ml of pyridine and 10 ml of a saturated ammonia solution are heated for 5 hours in a closed vessel at a temperature of 165 ° C. After cooling, it is poured into water, the mixture is boiled with active carbon and filtered in a hot state. The filtrate is concentrated under reduced pressure, the separated precipitate is filtered off after cooling and recrystallized from ethanol. 4-piperidinophenylacetic acid amide is obtained, which melts at 72-175 ° C. The starting material can be manufactured as follows. A mixture of 202 g of 4-fluoroacetophenol, 225 g of piperidine and 450 ml of dimethyl sulfoxide is heated for 48 hours in a steam bath, then they are cooled and poured into ice water. The precipitate obtained is filtered and recrystallized from hexane. The resulting 4-piperidinoacetophenone is melted.

Example 2. A mixture of 45 g of 4-pi1-peridino-acetophenone, 200 ml of morpholine, 8.5 g of sulfur and 2 g of α-toluene sulfonic acid is boiled with oriental stirring for 17 hours under reflux, then evaporated under reduced pressure. The residue is recrystallized from ethanol to obtain 4-peryridinophenylthioacetic acid morpholide, which melts at 156-158 ° C.

When uterine liquor is concentrated, a second precipitate is obtained, a filter and recrystallizing extract from isopropanol, a small amount of morpholide 4 Piperidinophenyl monothioglyoxylic acid is obtained, melting at 14.0-144 ° C.

Example 3. A mixture of 70 g of 4-pyrrolidinoacetopheloa, 250 mg of morpholine, 13.5 g of sulfur and 3 g of α-toluene sulfonic acid is boiled for 17 hours under refluxing, then evaporated at a reduced temperature. The residue is recrystallized from ethanol to obtain 4-p morpholide, irrolmidinophenyltiscetic acid, which melts at 168-171 ° C.

Example 4. A mixture of 50 g of 4-morpholinoacetophenone, 200 ml of morpholine, 9 g of sulfur and 2.5 g of l-tolzolsulfonic acid was boiled for 15 hours under reflux, then evaporated under reduced pressure. The residue is recrystallized from acetone to obtain 4-morpholinophenyl-acetic acid morpholide, which occurs at 164-156 ° C.

Example 5. A mixture of 100 g of 4-1-hexamethyleneMinoacetophenone, 300 L1l of morpholine, 25 g of sulfur and 2 g of α-toluene sulfo1; the acid is boiled for 16 hours under reflux, then concentrated under reduced pressure to about half the primary volume. Cool the concentrate and pour it into 500 ml of methanol; The temperature of the mixture is kept for 16 hours at approximately 4 ° C. and then filtered from the mixture. The residue on the filter is crystallized from methanol; the resulting 4-M-1hexamethylene-aminophenyl-acetic acid morpholfo melts at 127-129 ° C.

The starting material can be manufactured as follows.

A mixture of 100 g of 4-fluoroacetophenone, 150 g of hexametne amine and 250 ml of dimethyl sulfoxide is heated for 3 hours in a steam bath. The resulting solution is poured into ice and axt / degus the mixture with ether. The organic extract is dried, filtered and evaporated, yielding 4-1-hexamethylene-amino-acetophenone with mp. 44-46 ° C.

The corresponding 4-K-heptamethylamine minophenylthioacetic acid morpholide, which melts at 122-124 °, is made in an analogous manner. The starting material used can be made as follows.

A mixture of ilOO g of 4-fluoroacetopheion, 200 g of heptamethylenamine and 200 ml of dimethyl sulfoxide is heated for 24 hours in a steam bath and poured onto ice, the mixture is stirred for 15 minutes; the solid material is filtered off and washed with water; 4-M-heptamethylaminopheno acetophenone with mp is obtained. 45-47 ° C.

Example 6. A mixture of 1.20 g of 4- (4-met.ylpiperazino) -acetopheopop, 350 ml of morpholine, 40 g of sulfur and 5 g of l-toluenesulfonic acid was poured over 4 hours with a fridge, evaporated and evaporated under reduced pressure. Absorb the residue in water; the mixture is extracted with ether and the organic extract is evaporated. The residue is recrystallized from acetone to obtain 4- (4-methylcyperazino) -phenylthioacetic acid morpholide, which melts at 208-211 ° C.

The starting material can be manufactured as follows.

A mixture of 100 g of 4-fluoroacetophenone, 150 g of 1methyl (naphtha and 250 ml of methyl sulfoxide) is p-heated for 24 hours with an IB steam bath, then poured into ice-water. The resulting cage is filtered and washed with water; - Adetophenone melts at 98-99 ° C.

Using the appropriate starting materials and applying the methods given and the following (X P | Reamers, the following compounds are obtained:

3-chloro-4-morpholinocephlacetic acid, melting from a mixture of ether and petroleum ether at 125-126 °;

3-chloro-4-1 pyrrolidinophenylacetic acid, hydrochloride which melts after recrystallization from OMecii methanol and

ether at 194-196 °;

4-tyrrolidinophenyl | acetic acid, so pl. 138-141 °;

4- (3-pyrrilin-1-yl) - fepyl acetic acid, so pl. 162-165 ° C.

Example 7. A solution of 10 g of 4-piperidinothioacetic acid morpholide in 300 ml of acetone is treated dropwise while moving 25 ml of methyl iodide and boil the mixture for 3.5 hours with a reverse chiller, then cooled and filtered. The residue on the filter is dissolved in a mini-small amount of morpholine and heated in a steam bath until the formation of methyl mercaptan is stopped. Absorb the residue in water and heat the mixture.

10 min in a steam bath, then cooled and extracted with chloroform. The organic extract is dried, filtered and evaporated and the residue is recrystallized from a mixture of ether and hexane. Get mormydol 4-1PI | Peridinofacil |) Ksusna acid melts at 99-103 ° C.

Example 8. A mixture of 42 g of 4-piperidinophenylthioacetic acid morpholide and 250 ml of concentrated hydrochloric acid is slowly heated to the temperature of reflux and ki