SU263497A1 - METHOD FOR PRODUCING DERIVATIVES 3-KETO-a-4-KAR-BOXAMIDOALKYL-2,3-DIHYDRO-1,4-BENZOXAZINES - Google Patents

Description

The invention relates to the field of the preparation of new compounds which can be used in the pharmaceutical industry.

A method of producing 3-keto-cc-4 carboxamidoalkyl-2, 3-dihydro-1,4-benzoxazinoB of the general formula is proposed.

Kb

CHRrCO-N /

R,

where RI is a hydrogen atom or a lower alkyl radical, straight or branched;

Ra, Rg, Ri may have the same or different values — a hydrogen atom, a lower alkyl radical, a straight or branched chain, a halogen atom, or a lower alkyloxy radical;

Rs is a hydrogen atom or a lower alkyl radical or a N-dialkylcarboxamido group;

Re and Rv can have the same or different values — a hydrogen atom, an aryl radical or a lower alkyl or oxyalkyl radical, or Rg and Ry taken together form with the nitrogen atom to which they are bound, 5 or 6 carbon atoms heterocyclic radicals, which may contain, in addition to the nitrogen atom, other heteroatoms, such as pyrrolidyl, pineridyl, morpholyl or

piperazinyl Moreover, lower alkyl refers to an alkyl radical containing from 1 to 6 carbon atoms.

The method consists in the fact that 3-oxo-2,3-dihydro-1, 4-benzoxazine in the form of an alkali salt

metal of general formula

15

where RI, R2, Rs and R4 are as defined above,

M is an alkali metal, is subjected to interaction with a complex ester of the General formula

X -CHRs -COOR

where X is halogen, R is lower alkyl, Rs has; the above values, in an organic solvent medium, preferably in a tertiary butyl alcohol medium. If necessary, a small amount of iodide or

potassium bromide or lead this stage in a mixture of solvents containing approximately 50% dimethylformamide. The ester thus obtained is subjected to saponification in a water-alcohol medium at boiling in the presence of an alkali metal hydroxide, for example potassium hydroxide. The acid is obtained, which is treated first with thionyl chloride, taken in a small excess, in an inert organic solvent medium and, if necessary, in the presence of a catalyst, for example pyridine, dimethylformamide, at a temperature of 60-80 ° C, and then with an excess of ammonia or an amine of the general formula

/ Ko

HN R,

where Ro and RT are as defined above, in an inert penolic organic solvent such as chloroform. Products are isolated in a known manner. Exit 51 - 84%.

Example 1. Preparation of 3-keto-a-4-diegylenoxycarboxamidomethyl-2, 3 - dihydro-1,4benzoxazine.

In a flask with two tubes, equipped with a baffle, a reflux condenser and an ampoule with bromine, a solution of potassium tertiary butylate is prepared (by dissolving 6.55 g of metallic potassium in 250 cm of tertiary butyl alcohol). The solution, cooled to 40 ° C, is intensively transferred, 26 g of 3-oxo-2,3-dihydro-1,4-benzoxazine are added to it,

20.5 g of ethyl chloroacetate are added dropwise. The mixture is heated under reflux for 7 hours, the solvent is distilled off in vacuo, and the residue is taken up using approximately 200 cm of water.

The precipitate, partially crystalline, is extracted with ether, the organic solution is washed with water and it is dissolved (MgSO4), the solvent is distilled off, and the residue is crystallized from isopropyl oxide. The 3-oicco4-carbethoxymethyl-1,4-dihydrobenzoxazine thus obtained melts at 78 ° C. Yield 30.8 g (79%).

Calculated for di-HisNOj,%: C, 61.27; H 5.57; N 5.96.

Found,%: C 61.27; H 5.62; N 6.04.

20 g of the obtained ester is heated for 1 hour with reflux with 5.5 g of potassium in an aqueous-alcoholic medium (alcohol 200 cM water 15 slz), the solvent is distilled off in vacuum, the residue is dissolved in water, the solution treated with charcoal is filtered, then acidified with 4N hydrochloric acid. The precipitate is present, washed with water and in vacuum over phosphoric acid. Yield 16.9 g (92%). 3-Oxo-4-carboxymethyl-2, 3-dihydro-1,4-benzoxazine, purified by crystallization in ethanol, melts at 231 ° C.

Calculated for CioH9NO4,%: C 57.97; H 4.38; N 6.76.

gothionyl and 0.1 ogz anhydrous pyridine. The mixture is heated under reflux for 1 hour, the solvent and the excess thionyl chloride are distilled off in vacuo. The solid residue is dissolved in B 60 CM - anhydrous chloroform, and the solution is added dropwise to a chilled ice bath and a rapidly moving solution of morpholine (8.7 slgz) in chloroform (60 slgz). After the completion of the dropping, the mixture was stirred at room temperature for 2 hours, the precipitate was separated by filtration, then washed with chloroform. The combined organic solutions are washed by settling, first 4 N. HC1, then with water, 2 n. NaOn and again with water. After the substance (MgSOj), the solvent is distilled off, and the residue crystallizes from benzene. Yield 7.68 g (69.7%).

For analysis, 3-keto-a-4-diethylenoxycarboxamidomethyl-2, 3-dihydro-1,4-benzoxazine is dissolved at 110 ° C for 15 minutes; so nl 155--156 ° C.

Calculated for ScP1 (; - M2O4,%: C 60.86; H 5.84; N 10.14.

Found,%; C, 60.83; H 6.11; N 10.24. PRI mme R 2. Preparation of 3-oxo-H-4-dimethylcarboxamidomethyl-2, 3-dihydro-1,4-benzoxazine.

The acid chloride, isolated as described in example 1, obtained from 8.3 g of 3-oxo-4-carboxymethyl-2, 3-dihydro-1,4-benzoxazine in a solution of 60 sec of chloroform was added dropwise to a 22 slg of a solution of dimethanlamine in chloroform that was not rapidly displaced and cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours at room temperature, then filtered and the precipitate is washed with chloroform, the organic solution is washed successively with 4N. PS1, water, 2 n. NaOH, then nourish (MgS04). The solvent is evaporated, and the solid residue is crystallized from a mixture of benzene (one volume) and cyclohexane (two volumes); m.p. 125-126 ° C, yield 6.17 g (66%).

Calculated for Ci2Hi4N203,%: C 61.52; H 6.02; N 11.96. Found,%; C 61.43; H 6.12; N 11.99.

The table shows the constants of the compounds obtained in examples 1 and 2. The corresponding acid is obtained as described in example 1; by condensation of the potassium salt of Z-keto-6-chloro 2, 3-hydroxybenzoxazine and ethnyl chloroacetate, 3-keto-4-carbethoxymethyl-6-chloro-2,3-dihydro-1, 4-benzoxazine, t.nl. 115 ° C (crystallization from a mixture of cyclohexane-ether).

Calculated,%: C, 53.44; H 4.49; N 5.19; C1 13.15.

Found,%; C 53.29; H 4.48; N 4.97; C1 13.16.

As a result of the saponification of 3-keto-4-carbethoxymethyl-6-chloro-2, 3-dihydro-1,4-benzoxazine, 3-keto-4-carboxymethyl-6-hlrr-2,3-dihydro-1, 4-benzoxazine is obtained. ; m.p. 197 ° C (crystallization from ethyl acetate).

Characterization of compounds of general formula

R.

CHR.-CO-N

(R, R, H)

/ R,

 C1. %: calculated 13.20, found 13.30. C1,%: calculated 12.45, found 12.70.

Example 3. Getting 3-ke1 ..- penta.meilencarboxamidostil) -2,3-dihydro - 1,4-benuxasin.

As in Example 1, 44.7 g of 3-keto-2,3-dihydro, 4-benzoxazine is added to a solution of potassium tertiary butylate prepared from 12 g of 1 potassium metal and 350 sl tertiary-o) alcohol alcohol, then with perennially; : and 1 TREATED 54.3 g with; .- ethyl bromide ionate. The reaction is practically instantaneous (as indicated by the abundant precipitation of methyl bromide), it ends with heating with a flue for 1 hour during mixing. The solution, filtered and concentrated, dryness, forms a non-crystalline oil,

which is subjected to saponification without any purification.

The resulting crude ester is added to a water-alcohol solution (ethanol 500 sgls, water 40 slz) potassium (17.4 g). The reaction mass is heated for 2 hours with reflux, the solvent is distilled off in vacuo, the residue is dissolved with 400 cj / s water. The aqueous solution is extracted with ether, then acidified with hydrochloric acid. 3-oxo-4- (s-carboxyethyl) -2,3-dihydro1, 4-benzoxazn is precipitated, dried, washed with water, dried and crystallized from ethyl acetate (processed on animal charcoal). Yield 42 g (63.5%), so pl. 172 ° C.