DE1134981B - Process for the preparation of N-substituted 3-methoxy-4-carbamidomethoxyphenyl acetic acid alkyl and alkenyl esters - Google Patents

Description

GERMAN

PATENT OFFICE

kl. 12 ο 16

INTERNATIONAL KL.

C07c; d

F 31176 IVb / 12 ο

NOTICE DAY: MAY 6, 1960

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: 23 AU G TJ S T 1962

It has been found that N-substituted 3-methoxy-4-carbamidomethoxyphenyl acetic acid alkyl and alkenyl esters of the general formula

_K >

R "

-CH ₉ COOR

NOC- H ₂ CO- i _%

in which R is a low molecular weight alkyl or alkenyl radical, R 'and R "denote low molecular weight alkyl radicals, where R 'or R "can also be a hydrogen atom, or together with the nitrogen atom den Can form pyrrolidine or the piperidine radical, intravenously applicable, surprisingly short-acting Represent anesthetics that are different from those previously used exclusively for this purpose Barbituric acid derivatives in animal experiments due to a very rapid decrease in effectiveness and due to the lack of them the so-called »overhang«.

These compounds are prepared in a manner known per se by adding Homovanillinsäurealkyl- or alkenyl esters with the corresponding N-mono- or Ν, Ν-disubstituted haloacetamides or with other reactive esters N-substituted glycolic acid amides in the presence of alkaline condensation agents. Low molecular weight compounds are used as starting compounds Esters of homovanillic acid, such as the methyl, ethyl, propyl, butyl or allyl esters, as well as chloroacetamides, whose nitrogen atom is substituted by one or two alkyl radicals, these together with the nitrogen atom can also form the pyrrolidine or the piperidine radical. For example be N-propylchloroacetamide, Ν, Ν-diethylchloracetamide, ChloracetylpyiTolidin and -piperidin used. In order to avoid transesterification, one uses expediently as solvent the alcohol corresponding to the ester. A suitable condensing agent is preferably Sodium alcoholate. But you can also use hydroxyl-free solvents, such as toluene, work. In this case, the sodium compound used as the starting compound is first prepared Esters. A particularly preferred solvent for the reaction of these sodium phenates is dimethylformamide, in which the sodium compounds are readily soluble.

For the preparation of the N-substituted 3-methoxy-4-carbamidomethoxyphenyl-acetic acid alkyl or alkenyl esters can also be corresponding N-substituted S-methoxy ^ -carbamidomethoxyphenylacetic acids in a manner known per se with saturated or un-

Method of manufacture

of N-substituted 3-methoxy-

4-carbamidomethoxyphenylacetic acid alkyl

and alkenyl esters

Applicant:

Paint factories Bayer Aktiengesellschaft, Leverkusen-Bayerwerk

Dr. Rudolf Hiltmann, Dr. Hartmund Wollweber, Dr. Friedrich Hoffmeister and Dr. Wolfgang Wirth,

Wuppertal-Elberfeld have been named as the inventor

Esterified saturated low molecular weight aliphatic alcohols or also low molecular weight N-substituted S-methoxy-'i-carbamidomethoxyphenylacetic acid alkyl ester, z. B. the methyl ester, transesterify with other low molecular weight aliphatic alcohols.

The 3-methoxy-4-N, N-diethylcarbamidomethoxyphenylacetic acid-n-propyl ester which can be prepared according to Example 2 I was with the well-known 5-methyl-S-cyclohexenyl-N-methylbarbituric acid Sodium II compared. The following results were obtained in the dog when administered intravenously:

a) amount

b) stage of anesthesia *)

c) total anesthetic time ....

d) anesthetic time from VI to

IV in minutes

in ° / o of the total anesthetic time *)

e) DL ₅₀ mg / kg rabbit
given intravenously

40 mg / kg

VI 17 minutes

8 minutes

47 ° / o

80

II

40 mg / kg

VI

166 minutes

28 minutes

17%

70

*) Anesthesia stage VI corresponds, according to Magnus-Girndt, to deep anesthesia with complete lack of reflexes; Stage IV anesthesia corresponds to lateral position with preserved corneal and pinch reflex. The time from anesthesia stage VI to IV is roughly a standard for the period of time available for surgical interventions.

209 637/429

3 4

Similar results were obtained for rabbits. in a vacuum. After dissolving the residue in

It was found that when administering 200 ecm of dimethylformamide and adding 0.5 g of equal amounts with 3-methoxy-4-N, N-disodium iodide, ethylcarbamidomethoxyphenylacetic acid - η - propyl - is added dropwise to the solution with stirring. ^e at 130 C internal temperature 26.2 g Chloressigsäureester same depth of anesthesia is achieved as with the 5 N, N-diethylamide, and the mixture heated for an additional S-methyl-S-cyclohexenyl-N-methylbarbitursaurem Na 3 hours at 130 ⁰ C. After the same as in Example 1 trium, but with a much shorter overall work-up of the reaction mixture carried out under anesthesia. The total anesthesia time is 44.3 g of 3-methoxy-4-N, N-diethylcarbamido, the time from the onset of anesthesia to the disappearance of n-propyl methoxyphenylacetate as yellowish that of any narcotic symptoms, _{i.e. 10 oil with a bp} = 210 to 212 ° C.
until the point at which the animal regains itself

behaves perfectly normally. On humans over-example

wear, this point in time gives an indication of the need for a solution of 3.2 g sodium in 200 ecm

so-called "road capability". Methanol is given to 26 g of homovanillic acid methyl

As a result, the process products lead to a 15 ester (bp. _E = 149 ° C), the mixture evaporates in the vacancy much faster roadworthiness than the one and dissolves the residue in 200 ecm dimethyl comparison product, an advantage that is particularly evident in formamide. After the addition of 0.5 g of sodium iodide minor surgery in which only very short anesthesia 19.7g chloroacetic times required are added dropwise in the solution at 130 ⁰ C, are of crucial sawn acid-N, N-diethylamide and procedure further, as in the interpretation. Apart from the comparative product 20, example 1 is described. This gives 18 g of 3-both methoxy even when the remaining introduced intravenously to 4-N, N-diäthylcarbamidomethoxy-phenylessigsäuremeverabreichenden anesthetics such short scar methyl ester of boiling point _0i6 = 199 kosezeiten to 201 ⁰ C as pale yellow -. On reaching the depth of anesthesia, the colored oil.
surgical interventions permitted — not disclosed. In an analogous procedure, the following are obtained:

The obtainable by the process of the invention 25 3 - methoxy - 4 - carbpiperididomethoxyphenylessig compounds are the säurepropylester far as Kurznarkotikum, Kp _{0, 3} = 216-219 ⁰ C;.
used S-methyl-S-cyclohexenyl-N-methylbarbi- S-methoxy ^ -N-monoäthylcarbamidomethoxyphe-

Sodium turate is superior as a short-term anesthetic, such as propyl acetate., mp = 57 to 58 ° C;
from the table, which shows the results of anesthesia- S-methoxy ^ -N-monobutylcarbamidomethoxyphe-

try with rabbit shows clearly showing. 30 nylon propyl acetate, F. = 58 to 6O ⁰ C.

The superiority of following the method of

Compounds that can be produced in accordance with the invention are also given in Example 4

from the graphic representation. In this will

the course of anesthesia of S-methyl-S-cyclohexenyl 50 g of the 3-methoxy prepared according to Example 3

Sodium N-methylbarbiturate (50 mg / kg dog 35 4 - N ₅ N - diethylcarbamidomethoxyphenylacetic acid given intravenously, solid line) with the methyl ester are dissolved in 300 ecm of n-propanol, and the 3-methoxy-4-N, N-diethylcarb is anesthetized - After adding 0.1 g of sodium n-propoxide, ethyl amidomethoxyphenylacetate (100 mg / kg the mixture using an effective dog, given intravenously, dashed line) is heated to a column until no more methanol passes over. The hatched 40 in the graphic representation. After the excess propyl field has been distilled off, identifies the undesired "overhang" obtained with the comparison alcohols, the mixture is distilled in vacuo and the compound is obtained. receives 46 g of the 3-methoxy described in Example 2

The examples illustrate the process of the invention. 4 - N ₅ N - diethylcarbamidomethoxyphenylacetic acid -

n-propyl ester of boiling point. _0l7 = 210 to 212 ⁰ C.

Example ¹ * Example 5

21 g of ethyl homovanulate are added to a solution of 2.3 g of sodium in 100 ecm

Solution of 2.3 g of sodium in 100 ecm of ethanol. After ethanol, 21 g of ethyl homovanulate are added

after distilling off the alcohol in vacuo, 50 and 0.5 g of sodium iodide are dissolved. The mixture is heated

the flask residue in 100 ecm dimethylformamide. with stirring on the reflux condenser and dropwise 15 g

After adding 0.5 g of sodium iodide, chloroacetic acid-N, N-diethylamide is instilled. After further

with stirring into the heated at 13O ⁰ C solution of 15 g 8 hours of heating to boiling distilling the

Chloroacetic acid-N, N-diethylamide and heats the Mi- ethanol in vacuo and takes the residue in

until the alkaline reaction dissolves water and benzene. The separated benzene layer

has faded. This is done after about three hours with dilute caustic soda and water.

heat the case. Wash from the cooled reaction mixture and dry with sodium sulfate. After this

if the precipitated salts are removed by distilling off the solvent, the distillation is carried out

suck. After the dimethylform residue has been distilled off in vacuo, 21 g of the

amides in vacuo are fractionated in vacuo and 60 game 1 described S-methoxy-NjN-diethylcarb-

receives 22.5 g of 3-methoxy-4-N, N-diethylcarbamidometh- amidomethoxy-phenylacetic acid ethyl ester of bp ", ₆

Ethyl oxy-phenylacetate with a _{b.p. 0i6} = 204 to = 204 to 207 ⁰ C.
207 ⁰ C as a yellowish, water-insoluble oil. Example 6

Example 2 _{6g 2Q g} 3_Methoxy-4-N, N-diä% lcarbamidomethoxy-

To a solution of 4 g of sodium in 200 ecm phenylacetic acid (F. = 119 to 12O ⁰ C), which from the

n-propanol is added to 39 g of homovanillic acid n-propyl methyl ester obtained by saponification with alkali

ester (bp. ₄ = 160 to 162 ° C) and if the mixture is steamed, 200 ecm 3% chlorine water

material-containing n-propyl alcohol heated under the reflux condenser for 8 hours. After the solvent has been distilled off, the residue is taken up in benzene, the benzene solution is washed with sodium carbonate solution and water and the benzene solution is dried with sodium sulfate. After the benzene has been distilled off, the residue is distilled in vacuo and 19.8 g of S-methoxy ^ -NN-diethylcarbamidomethoxyphenylacetic acid n-propyl ester with a boiling point of _{0 7} = 210 to 212 ° C. is obtained.

Example 7

_{54.4 g of homovanillic acid n-butyl ester (bp. Oil} = 145 to 146 ° C.) and 0.5 g of sodium iodide are added to a solution of 5.2 g of sodium in 200 ecm of n-butanol. The mixture is heated on the reflux condenser and 33.8 g of chloroacetic acid-N, N-diethylamide are added dropwise. After the mixture has been heated to boiling for a further eight hours, it is allowed to cool, filtered off with suction and the residue is washed with n-butanol. The n-butanol is distilled off from the filtrate in vacuo, the residue is taken up in benzene and the benzene solution is washed with dilute sodium hydroxide solution and water. After drying the benzene solution with sodium sulfate and distilling off the solvent, the residue is distilled under vacuum to give 52 g of 3-methoxy-4 - N, N - diäthylcarbamidomethoxy - phenylacetic acid n-butyl ester, bp = 194 ⁰ C. _Oil.

Example 8

50 g of 3-methoxy-4-N, N-diethylcarbamidomethoxyphenyl acetic acid methyl ester, prepared according to Example 3, are dissolved in 300 ecm of allyl alcohol and the mixture, after adding 0.1 g of sodium, is heated in the cooler until no more methanol passes over. After distilling off the excess allyl alcohol, the residue is distilled under vacuum, obtaining 43 g of 3-methoxy -A- N, N-diäthylcarbamidomethoxyphenylessigsäureallylester from Kp. _{0, 8} = 208 to 210 ° C.

Example 9

42 g of potassium carbonate are added to a solution of 62.75 g of homovanillic acid propyl ester in 115 ecm of acetone. The mixture is heated to the boil while stirring, 44.2 g of Ν, Ν-diethylchloroacetamide are added dropwise and the mixture is kept at the boiling temperature overnight. After cooling, it is filtered off with suction and the acetone is distilled off from the filtrate, finally in vacuo. The residue is taken up in methylene chloride, the solution obtained is washed with 10% sodium hydroxide solution and water and dried with potassium carbonate. The residue remaining after the solvent has been distilled off is distilled in vacuo. This gives 80.2 g of 3-methoxy-4 - N, N - diäthylcarbamidomethoxy - phenylacetic acid n-propyl ester, bp _0i7 = 210 to 212 ⁰ C..

Tabel

link DL ₅₀ mg / kg,
Rabbits
intravenous
given Amount to
achievement
from anesthesia
stage V Duration of
anesthesia
stage V Minutes Amount to
achievement
from anesthesia
stage VI Duration of
anesthesia
stage VI Minutes 1. S-methyl-S-cyclohexenyl-N-methylbarbitur- -70 50 mg / kg 60 60 mg / kg 65 acidic sodium Rabbits Minutes Rabbits Minutes 2. 3-methoxy-4-N, N-diethylcarbamidomethoxy- > 180 90 mg / kg 13th 150 mg / kg 15th phenylacetic acid methyl ester Rabbits Minutes Rabbits Minutes 3. 3-methoxy-4-N, N-diethylcarbamidomethoxy- -80 30 mg / kg 8th 60 mg / kg 17th allyl phenylacetate Rabbits Minutes Rabbits Minutes 4th S-methoxy ^ -piperididomethoxyphenyl acetic- -70 40 mg / kg 13th 60 mg / kg 16 acid propyl ester Rabbits Minutes Rabbits Minutes 5. S-methoxy ^ -N-monoäthylcarbarnidometh- > 90 75 mg / kg 12th 90 mg / kg 10 propyl oxyphenylacetate Rabbits Minutes Rabbits Minutes 6th 3 - methoxy- 4 - N- monobutylcarbamidometh - -50 30 mg / kg 7th 40 mg / kg 9 propyl oxyphenylacetate Rabbits Minutes Rabbits Minutes 7th 3-methoxy-4-N, N-diethylcarbamidomethoxy- > 80 50 mg / kg 10 70 mg / kg 16 ethyl phenylacetate Rabbits Minutes Rabbits Minutes 8th. S-methoxy ^ -carbpyrrolididomethoxyphenyl- -70 40 mg / kg 13th 60 mg / kg 16 acetic acid n-propyl ester Rabbits Rabbits

Claims (1)

PATENT CLAIM: Process for the preparation of N-substituted 3-methoxy-4-carbamidomethoxyphenylessigsäurealkyl- and alkenyl esters of the general formula R '. R " H.CO - _; —CH ₂ COOR NOC-H ₂ CO- in which R is a low molecular weight alkyl or alkenyl radical and R 'and R "denote low molecular weight alkyl radicals, where R' or R" can also be a hydrogen atom, or can form the pyrrolidine or the piperidine radical together with the nitrogen atom, characterized in that one either a) Homovanillic acid esters of the general formula CH ₃ O ^
HO— ' -CH ₂ COOR in which R has the above meaning, with bonds of the general formula ^R '\ , NCOCH ₂ X _R "/ in which R 'and R "are as defined above and X is a reactive group, in the presence of alkaline condensing agents in a known manner or that one b) compounds of the general formula R 'CH ₃ O-,'-'N _n -CH ₂ COOH ^ NCOCH ₂ O- ¹ ! * 5 R '" in which R 'and R "have the above meaning, with alcohols of the general formula ROH, in which R has the above meaning, in itself esterified in a known manner or that one c) esters of the general formula R '. R " CH, 0 - - \ - CH ₂ COOR "' ^ -COCH ₂ O- transesterified in a manner known per se with an alcohol of the general formula ROH, and in the general formulas R ', R "and R have the meaning given above and R"' is a low molecular weight Alkyl radical with fewer carbon atoms than R is. 1 sheet of drawings © 209 637/429 8.62