DE1445969B - Process for the preparation of basic 3,4,5 Tnmethoxybenzoic acid esters - Google Patents

Description

HO-CH ₂ -C-CH ₂ -B have reacted in the presence of alkalis in a two-phase mixture of water and water-immiscible solvent or in an inert solvent.

in which R ₁ , R ₂ and B have the meaning given above. The present invention relates to a process for the preparation of basic 3,4,5-trimethoxybenzoic acid esters of the general formula

CH ₁ O

CH ₃ O

CO-O-CH, -C-CH, -B

in which R ₁ denotes a methyl or ethyl group, R ₂ denotes an ethyl, propyl, phenyl or benzyl group and B denotes a dimethyl or diethylamino, pyrrolidino, piperidino or morpholino group, which are produced by in an known way 3,4,5-trimethoxybenzoyl chloride with aminopropanols of the general formula

τ_τ / ~ \ / " ¹ TJT Γ * r ^ XJ TJ

rl KJ ν-.η-2 ^ ^ - * ^ 2 D

R ₂

in which R ₁ , R ₂ and B have the meaning given above, is reacted in the presence of alkalis in a two-phase mixture of water and water-immiscible solvent or in an inert solvent.

In the modern scientific literature, numerous are derived from 3,4,5-trimethoxybenzoic acid Compounds with neuropharmacological effects have become known. Basic substituted Alkyl esters have a dampening effect on the nervous system. It is characterized by the fact that the alkyl chains such esters are unbranched. It was therefore not foreseeable that the introduction of a Quaternary C-atom in / ^ - position of the C-propyl chain, whose Substituents have more than 2 carbon atoms, compounds with incomparably stronger pharmacological Effect with significantly lower toxicity.

The compounds according to the process show against known basic substituted alkyl esters • the 3,4,5-trimethoxybenzoic acid with unbranched, basic substituted alkyl groups is an essential one lower toxicity and unexpected superior effects on the central and vegetative nervous system, which are expressed in the sedative and antihypertensive efficacy, as can be seen from the attached Tables I and II, especially when comparing the therapeutic index.

about the sedative and antihypertensive effects of structurally comparable compounds report among others:

1. G. Palazzo, L. Bizzi, C. Pozzati, Proc. Intern. Congr. Neuro-Pharm., 1st. Rome 1958, pp. 378 to 390, referenced: Chem. Abstr., Vol. 54, pp. 13402 d-f (1959);

2. J. Supniewski, K. Bednarz, J. Krup in ska, Dissertationes Pharm., 10, pp. 191 to 211 (1958), reported Chem. Abstr., Vol. 53, p. 7435 ce (1959). ~ Φ '

Consistent with the previously published information and our own investigations the 3,4,5-trimethoxybenzoic acid (3-morpholinopropyl) ester used for comparison the state of the art with regard to its sedative effect.

55

60

CH ₃ O CH ₃ O CH ₃ O

Table I.

CO--CH, -C-CH, -B

connection R. R ₂ B. QH ₅ N QH ₅ DL ₅₀ / mg / kg Sedatives
effectiveness
ED ₅₀ / mg / kg More therapeutic
index QH ₅ <] example 1 QH ₅ C ₂ H ₅ /
N
\ ^ ^N \ / ° ^N \ / ° 3360 29.57 1: 114 QH ₅
/ Example 2 QH ₅ QH ₅ 2125 20.19 1: 105 Example 3 QH ₅ QH ₅ 1880 15.98 1: 117.6 Example 4 QH ₅ C ₆ H ₅ CH ₂ 4280 59.92 1: 71.4 Example 5 QH ₅ C ₆ H ₅ 2200 29.7 1:74 Reference substance H H 1080 40.5 1: 26.7

Table II

CH ₃ O CH ₃ O
CH ₃ O

R ₁

CO-O-CH ₂ -C-CH ₂ -B

R ₂

Connection ^; R, R ₂ B. /
N QH ₅ DL ₅₀ / mg / kg Blood pressure
lowering
effectiveness
ED ₅₀ / mg / kg More therapeutic
index QH ₅ example 1 QH ₅ QH ₅ 3360 2 ■ 1680 '4-' Example 2 QH ₅ C ₂ H ₅ 2125 1.95 1089 Example 3 QH ₅ QH ₅ 1880 2.6 723

continuation

connection R ₁ QH ₅ CH ₂ B. QH ₅ /
N QH ₅ DL _M) / mg kg Blood pressure
lowering
Effective wedge
ED ₅₀ mg kg More therapeutic
index N <Q Example 4 QH ₅ QH ₅ ^N \ / ⁰ 4280 2.6 1646 H Example 5 QH ₅ 2200 3.0 733 Reference substance H 1080 4.75 227

The acute toxicity is given in the tables with DL ₅₀ (mg / kg). This is the amount of substance which, after subcutaneous administration, causes the death of 50% of the test animals (white mice) within 24 hours.

To determine the sedative effect, the percentage prolongation of the hexobarbital sleep *) was determined by the method of Holten and L arse η (Acta Pharmakologica et Toxicologica 12 [1956], pp. 346 to 363) by adding the test substances in doses of 1, 2 and 5% of the DL ₅₀ were administered 30 minutes before the subcutaneous application of 100 mg / kg hexobarbital sodium and the prolonged sleep was measured in relation to animals that had not been pretreated. The ED ₅₀ (= effective dose which causes 50% sleep prolongation) was determined graphically on the basis of the dose-effect curve.

The blood pressure was measured in blood on rabbits anesthetized with urethane - 1 g / kg (25% solution) iv - on the common carotid artery using a mercury manometer. The substances to be tested were injected intravenously into the external jugular vein, as described in L. T. Her, "Pharmakologische Methode" (1949), pp. 212-227. The ED ₅₀ (= effective dose which causes a 50% reduction in blood pressure) was determined graphically from the dose-effect curve.

The following examples are intended to explain the invention:

example 1

3,4,5 - trimethoxybenzoic acid - (2,2 - diethyl - 3 - diethylamino-propyl-1) -ester, 28 g 2,2-diethyl-3-diethylamino-propanol-1 and 6 g caustic soda, dissolved in 80 ml of water, are placed together in a 1-1 three-necked flask. With ice cooling, 34.5 g of 3,4,5-trimethoxybenzoic acid chloride, dissolved in 200 rhi absolute benzene, are then added dropwise. The reaction mixture is then refluxed for 2 hours. After cooling, the benzene phase is separated from the aqueous phase. The watery one. Phase is extracted several times with benzene. The benzene phases are combined, extracted three times with 50 ml of 15% sodium hydroxide solution each time, then washed neutral with water, _{dried with Na 2} SO ₄ and concentrated. The residue is distilled in a high vacuum.
Yield: 40 g = 70% of theory, n'j = 1.5103.

Example 2

3,4,5-trimethoxybenzoic acid (2,2-diethyl-3-pyrrolidino-propyl) ester, 27.8 g of 2,2-diethyl-3-pyrrolidinopropanol-1 and 6 g of caustic soda, dissolved in 80 ml of water, are placed together in a 500 ml three-necked flask. With ice cooling, 34.5 g = 0.15 mol of trimethoxybenzoic acid chloride, dissolved in absolute benzene, are then added dropwise. When the entry is complete, the reaction mixture is refluxed for a further 2 hours. The benzene phase is then separated from the aqueous phase. The aqueous phase is extracted several times with benzene. The two benzene phases are combined, extracted three times with 50 ml of 15% sodium hydroxide solution each time, then washed neutral with water, _{dried with Na 2} SO ₄ and concentrated. The residue is taken up in alcohol and recrystallized with the addition of activated charcoal.

Yield: 22.5 g = 39.5% of theory, colorless crystals with a melting point of 68 ^° C.

Example 3

*) "Hexobarbital" = unprotected international abbreviation for S-f-Cyclohexen-1-yll-S-methyl-N-methylbarbituric acid.
The therapeutic index = DL ₅₀ : ED ₅₀ .

3,4,5 - trimethoxybenzoic acid (2,2-diethyl - 3-morpholino-propyl) ester, 30.2 g of 2,2-diethyl-3-morpholinopropanol- (l) and 16 g of triethylamine are dissolved in 200 ml of dried chloroform. In the ice-cold Mixture is a solution of 35 g of 3,4,5-trimethoxybenzoic acid chloride in 100 ml of dried Chloroform was added dropwise. Then remove the ice cooling and heat for 30 minutes later on for 1 hour on the steam bath.

The cooled reaction mixture is extracted successively with dilute sodium hydroxide solution and water. The separated benzene phase is dried over sodium sulfate. After removing the benzene the residue crystallizes by distillation after cooling.

Yield: 35 g = 59% of theory, colorless crystals with a melting point of 56 ° C. from ether-petroleum ether.

Example 4

Analogously to the procedure described in Example 3, 36 g of 2-ethyl-2-benzyl-3-diethylaminopropanol (l) reacted with 35 g of 3,4,5-trimethoxybenzoyl chloride with the addition of 15 g of triethylamine, wherein 3,4,5-trimethoxybenzoic acid (2-benzyl-2-ethyl-3-diethylaminopropyl) ester is obtained.

Yield: 35 g = 55% of theory, a liquid, boiling 0.2 21O ⁰ C, η% = 1.5406..

Example 5

As described in Example 3, the reaction of 2-ethyl-2-phenyl-3-pyrrolidinopropanol- (l) with 3,4,5-trimethoxybenzoyl chloride and triethylamine 3,4,5-trimethoxybenzoic acid (2-ethyl-2-phenyl-3-pyrrolidino-propyl) ester.

. Yield: 54% of theory, liquid from ίο Kp 0.01 204 ⁰ C, iff = 1.5530.

209 514/335

Claims (1)

Claim: Process for the preparation of basic 3,4,5-trimethoxybenzoic acid esters of the general formula R ₁ CO O CH-> C CH-i B in which R ₁ denotes a methyl or ethyl group, R ₂ denotes an ethyl, propyl, phenyl or benzyl group and B denotes a dimethyl or diethylamino, pyrrolidino, piperidino or morpholino group, characterized in that one is known per se Way 3,4,5-trimethoxybenzoic acid chloride with aminopropanols of the general formula