DE1057122B - Process for the preparation of heterocyclic esters - Google Patents

Description

GERMAN

The present invention relates to a process for the preparation of heterocyclic esters of the general formula

R O

! Il y ^N \

R'-C-C-O-CH ₂ -Cf) (CH _a ) "I

ι \ /

R "

where R is an aryl radical, R 'is an alkyl, cycloalkyl, aryl radical or a sulfur-containing hoterocyclic radical, R "is a hydrogen atom or a hydroxyl group and η is the integer 2 or 3. The invention also includes the preparation of salts and quaternary ammonium compounds of such esters .

The compounds according to the invention show spasmolytic activity. Have some of the connections also proved to be useful local anesthetics. The new compounds as well as their salts and quaternaries Ammonium compounds are high-melting solids that are soluble in water.

The compounds can easily be prepared by condensation of a corresponding 2-chloromethyl-3,4,5,6-tetrahydropyrimidine or 2-chloromethylimidazoline with a Acid of the following general formula, in which the letters have the same meaning as in formula I, produced in the presence of potassium iodide:

R O

R '- C-

R "

OH

II

The halogen atom of the heterocyclic halogen compound can also be an iodine or bromine atom, however the chlorine compound is preferred because of its ease of preparation and accessibility. For the invention Implementation suitable acids are z. B. benzilic acid, α-phenyl-a-cyclopentyl-oxyacetic acid, α-phenyl-α-cyclohexyl-oxyacetic acid, α-phenyl-a-cyclohexylacetic acid, a-naphthyl-a-phenylacetic acid, dinaphthylacetic acid, Dinaphthyl-oxyacetic acid, a-phenyl-caproic acid and a-phenyl-a-oxycaproic acid, d. H. such acids, in where the character R of the above general formula is an aryl radical, such as a phenyl, naphthyl or diphenyl radical, means, R 'an aryl radical, such as a phenyl or naphthyl radical, an alkyl radical, such as a methyl, Ethyl, propyl, butyl, isobutyl or octyl radical, a cycloalkyl radical such as a cyclopentyl or cyclohexyl radical, or a sulfur-containing heterocyclic radical, such as a thienyl or thopyranyl radical.

The reaction can be carried out in a manner known per se and in various solvents, including methanol, processes for the preparation
of heterocyclic esters

Applicant:

Chas. Pfizer & Co., Inc.,
Brooklyn, NY (V. St. A.)

Representative: Dr. W. Beil, lawyer,
Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
V. St. v. America 19 August 1954

John Andrew Faust and Melville Sahyun,

Santa Barbara, Calif. (V. St. Α.),

have been named as inventors

Ethanol, isopropanol, propanol, butanol and acetone. One method is that the acid and the aminoalkyl halide are allowed to react with one another in a suitable solvent. A useful modification of this process is to react a metal salt of the acid with a salt the aminoalkyl halide; in this case, the metal salt formed as a by-product in the course of the process must be separated off prior to the isolation of the process product. Sometimes it is useful with these Working methods to condense in the presence of potassium iodide, which initiates the reaction and acts as a catalyst works. This is a preferred embodiment of the present invention. The reaction temperatures are preferably above 50 ° C so that the reaction does not take too long. The reaction is common at elevated temperatures finished in 4 to 10 hours. After the reaction has ended, the reaction mixture is filtered to remove the to isolate solid particles formed therein, or ether is added to precipitate the solid particles. These Solid particles represent salts of the esters according to the process, the acid radical of which is from the halogen atom of the used Starting material originates, and can be separated by filtration, centrifugation or decanting and recrystallized from a suitable solvent.

The free esters according to the present invention can be prepared by dissolving the salt in a suitable solvent, Neutralization of this solvent with alkali, e.g. B. Soda or caustic soda, and taking off the resulting Mixture with ether can easily be isolated.

90 J 510/442

When the ether evaporates, the free ester remains, which is usually a high-boiling liquid or a is a low-melting solid body.

Salts, e.g. B. the hydrochloride, hydrobromide, hydroiodide, Acetate, nitrate, sulfate, lactate, citrate, phosphate and bitartrate, and quaternary ammonium salts, e.g. B. the methyl iodide, methyl bromide, methyl chloride, p-toluenesulfonate and dimethyl sulfate, are easily prepared by combining a solution of the free ester with a solution the appropriate salt-forming compound in contact. When you combine the salt, if you the correct solvent or solvents will normally fail, or the solvent is removed by evaporation, leaving behind the acid addition salt or the quaternary ammonium salt.

Preferred compounds are those in which R, R ', R "and η in the general formula I shown above have the following meanings:

R. R ' R " η Phenyl Cyclohexyl H 3 Phenyl Cyclohexyl OH 3 Phenyl Cyclohexyl OH 2 Phenyl Butyl OH 3 Phenyl Phenyl OH 3 Phenyl Phenyl H 3 Phenyl 2-thienyl OH 3 Phenyl Phenyl H 2 Phenyl Phenyl OH 2

30th

Esters of heterocyclically substituted methanol obtained by reacting heterocyclically substituted methyl halides are produced with salts of organic acids are already known. Own these connections however antihypertensive effectiveness. An antihypertensive efficacy occurs in accordance with the procedure obtained substances. It would also be just an extremely undesirable side effect, the administration of the antispasmodic and antisecretory compounds according to the invention It would be impossible to treat patients with low blood pressure, as one runs the risk of having severe Health impairment related circulatory collapse could not risk.

The new substances which can be produced according to the process therefore have different properties than the known compounds with a comparable constitution. In doing so, it is precisely the lack of the known connections that makes them own antihypertensive effect to safely applicable agents with desired antisecretory and antispasmodic efficacy.

The following examples are intended to illustrate the present invention.

example 1

ct-Cyclohexyl-ct-phenylacetic acid-p.'i.S.ö-tetrahydropyrimidyl- (2) -methyl] -ester-hydrochloride

a) 2-chloromethyl-3,4,5,6-tetrahydropyrimidine hydrochloride.

A solution of 7.5 g (0.1 mol) of 1,3-diaminopropane in 90 ecm of ethanol was cooled to 0 ° C. with stirring and in the course of one hour in portions with 15.8 g (0.1 mol) of chloroethyliminoethyl ether hydrochloride offset. After stirring the mixture for 2 hours at 0 ° C., it became more n-ethylalcohol by adding 68 ecm 2 Hydrochloric acid acidified, the temperature being kept at 0 to 5 ° C. Then the mixture was allowed to stand warm up to 20 ° C and stirred it for 1 hour, filtered it and evaporated the filtrate in vacuo, until a solid residue was obtained, which then turned off

55 25 ecm isopropanol was recrystallized. The yield of 2 - chloromethyl - 3,4,5,6 - tetrahydropyrimidine hydrochloride, a crystalline solid, was 8 g (corresponding to 47% of theory).

b) A solution of 4.1 g (0.019 mol) of a-cyclohexyl-phenylacetic acid and 2.5 g (0.019 mol) of 2-chloromethyl-3,4,5,6-tetrahydropyrimidine hydrochloride in 100 ecm of isopropanol containing 0.5 g of potassium] 'odide was 6 hours boiled long under reflux, whereupon the mixture was filtered, the filtrate was concentrated to about 30 ecm and then diluted with 100 ecm of ether. The separating white solid body, a-cyclohexyl-a-phenylacetic acid - [3,4,5,6 - tetrahydropyrimidyl - (2) - methyl] - ester hydrochloride, was isolated and recrystallized from an ethanol-ether mixture, giving 2.3 g of the product received; F. 234 to 235 ° C.

Example 2

α-Cyclohexyl-α-phenylglycolic acid- ^ S-dihydroimidazolyl- (2) -methyl] ester hydrochloride

A mixture of 4.7 g (0.02 mol) of a-cyclohexyl-a-phenylglycolic acid, 2.5 g (0.02 mol) of 2-chloromethyl-imidazoline hydrochloride, 0.2 g potassium iodide and 60 ecm isopropanol was refluxed for 6 hours. After the alcohol had evaporated from the solution, the The residue is dissolved in water and the solution is freed from neutral components by extraction with ether. After this the solution had been made alkaline with sodium hydroxide solution, the deposited oily base was drawn with it Ether and treated the dry ethereal solution with a solution of hydrogen chloride in ether. Of the The resulting solid body was separated off by filtration and recrystallized from an alcohol-ether mixture, 1.4 g of α-cyclohexyl-α-phenylglycolic acid [4,5-dihydroimidazolyl- (2) methyl] ester hydrochloride obtained, which melted at 207 to 208 ° C with decomposition.

Example 3

1-phenyl-1-oxycaproic acid [3 ', 4', 5 ', 6'-tetrahydropyrimidyl (2') methyl] ester hydrochloride

To a solution of 4.2 g (0.02 mol) of 1-phenyl-1-oxycaproic acid and 3.0 g (0.022 mol) of 2-chloromethyl-3,4,5,6-tetrahydropyrimidine in 40 ml of isopropanol were added 0.1 g of potassium iodide, the mixture refluxed for 4 hours, the solution nitrated while hot and diluted them after cooling with ether. The precipitated solid was isolated and recrystallized from isopropanol. 3.2 g of 1-phenyl-1-oxycaproic acid [3 ', 4', 5 ', 6'-tetrahydropyrimidyl (2') methyl] ester hydrochloride were obtained in this way. F. 198 to 199 ° C.

Analysis:

Calculated
found

N 8.22%, Cl 10.40%;
N 8.03%, Cl 10.31%.

Example 4

Benzilic acid [3,4,5,6-tetrahydropyrimidyl (2) methyl] ester hydrochloride

A mixture of 4.8 g (0.02 mol) of benzilic acid, 3.0 g (0.034 mol) of 2-chloromethyl-3,4,5,6-tetrahydropyrimidine, 0.5 g of potassium iodide and 125 ecm of isopropanol was refluxed for 6 hours, whereupon the The mixture was filtered, the filtrate was cooled and the precipitated solid was isolated and extracted from 35 ecm of methanol recrystallized to which a small amount of sodium bisulfite had been added. 3.0 g (corresponding to 42% of theory) colorless crystals of benzilic acid - [3,4,5,6 - tetrahydropyrimidyl - (2) - methyl] ester hydrochloride obtained from mp 218 to 219 ° C (with decomposition).

Example 5

Benzilic acid [4,5-dihydroimidazolyl- (2) methyl] ester hydrochloride

A mixture of 8.7 g (0.04 mole) benzilic acid, 4.8 g (0.04MoI) 2-chloromethylimidazoline, 1.0g potassium iodide and 125 ecm of isopropanol was refluxed for 45 minutes boiled for a long time, in the course of which a solid body separated from the mixture. The mixture was cooled filtered and recrystallized the resulting solid body from 350 ecm of ethanol. This gave 6.5 g, correspondingly 47% of theory, benzilic acid [4,5-dihydroimidazolyl- (2) methyl] ester hydrochloride, M.p. 202 to 203 ° C (with decomposition). Another recrystallization from 60 ecm of methanol gave 4.4 g of colorless needles which melted at 211 to 212 ° C. (with decomposition).

Example 6
Dipheny 1-acetic acid- [3,4,5,6-tetrahydropyrimidy 1- (2) -

methylj-ester hydrochloride

A mixture of 4.24 g (0.02 mol) of diphenylacetic acid, 3.0 g (0.02 mol) of 2-chloromethyl-3,4,5,6-tetrahydropyrimidine, 0.5 g of potassium iodide and 125 ecm of isopropanol were refluxed for 5 hours and then nitrated. After cooling, a solid separated from the filtrate, which weighed 4.5 g, corresponding to 65% of theory, and after recrystallization from ethanol at 237 to 238 ° C (with decomposition) melted. This substance is diphenylacetic acid [3,4,5,6-tetrahydropyrimidyl- (2) -methyl] -ester- hydrochloride.

Example 7
a-Phenyl-a-thienyl- (2) -glycolic acid- [3 ^/ , 4 ', 5 ^/ , 6'-tetra-

hydropyrimidyl (2) methyl] ester hydrochloride
A mixture of 5.8 g (0.025 mol) of a-phenyl-a-thienyl- (2) -glycolic acid, 3.5 g (0.025 mol) of 2-chloromethyl-3,4,5,6-tetrahydropyrimidine, 0.5 g of potassium iodide and 100 ecm of isopropanol were refluxed for 6 hours, the last 15 minutes of which in the presence of decolorizing charcoal, then filtered and the filtrate was cooled, whereupon a solid separated out that weighed 3.5 g (corresponding to 38% theory) and after recrystallization from a methanol-ether mixture at 213 to 214 ⁰ C (with decomposition) melted. This substance was a-phenyl-a-thienyl- (2) -glycolic acid- [3 ', 4 ^/ , 5', 6'-tetrahydropyrimidyl- (2 ') -metbyl] -ester-hydrochloride.

Example 8
Diphenylacetic acid [4,5-dihydroimidazolyl- (2) -

methyl] ester hydrochloride g ₀

A solution of 8.5 g (0.04 mol) of diphenylacetic acid and 4.8 g (0.04 mol) of 2-chloromethylimidazoline in 80 ecm Isopropanol was refluxed for 9 hours. The solid was separated off, the residue taken up in water and extracted the undissolved with ether. After drying the essential Solution over anhydrous magnesium sulfate, it was treated with a solution of hydrogen chloride in ether. The oily hydrochloride which precipitated out was recrystallized from an ethanol-ether mixture, 1.0 g Diphenylacetic acid [4,5-dihydroirmdazofyl- (2) methyl] ester hydrochloride which melted at 201 to 202 ° C.

Example 9

a-Cyclohexyl-a-phenylglycolic acid-pAS ^ -tetra-

hydropyrimidyl (2) methyl] ester hydrochloride

The free base 2-chloromethyl- (3,4,5,6) -tetrahydropyrimidine was obtained by treating its hydrochloride salt (prepared according to Example 1, a) with aqueous sodium hydroxide solution in the presence of ether. The mixture was stirred vigorously while cooling with ice, whereupon the free base was recovered from the ethereal layer. 2.7 g (0.02 mol) of the free base were dissolved in 1 cm of isopropanol and treated with 4.7 g (0.02 mol) of α-cyclohexyl-ct-phenylglycolic acid. A clear solution resulted which was refluxed with stirring for 5 hours. In the course of this time, the product separated from the solution as a white crystalline solid body, a sample of which _{melted after recrystallization from 90 ° / 0} isopropanol at 246 to 246.8 ° C.

Analysis: C ₁₉ H ₂₇ O ₃ N ₂ Cl (molecular weight 367)

Calculated Cl 9.66%,

found Cl 9.64%; Molecular weight determined

by titration with perchloric acid in anhydrous medium: 365.

Claims (1)

Claim: Process for the preparation of heterocyclic esters of the general formula R O R'-CCO-CH ₂ R " , N _n TNT where R is an aryl radical, R 'is an alkyl, cycloalkyl, aryl radical or sulfur-containing heterocyclic radical, R "is a hydrogen atom or a hydroxyl group and η is the integer 2 or 3, by reacting methyl halides substituted by a heterocyclic radical with substituted monocarboxylic acids and of salts or quaternary ammonium compounds of such esters, characterized in that a compound of the general formula X-CH, , N _n "- (CH ₈ ). where X is a chlorine, bromine or iodine atom and η is the integer 2 or 3, with an acid of the general formula R O R'-CC-OH
i
R " wherein R, R 'and R "have the above meaning, preferably reacted in the presence of potassium iodide as a catalyst and optionally the ester salt obtained in this way in a conventional manner in the free ester or a quaternary ammonium compound is convicted. Considered publications:
British Patent No. 614 772. © 909 510/442 5.59