DE1024505B - Process for the preparation of new bis-carbamic acid esters - Google Patents

Description

GERMAN

It is known that certain synthetically obtained carbamic acid esters contain a quaternary nitrogen atom aromatic or heterocyclic oxy compounds derived, for example, from m-dimethylaminophenol or derive from 3-oxypyridine, are strong cholinesterase inhibitors and are natural in place of the occurring alkaloid eserin can be used medicinally.

It has been found that the previously unknown compounds of the general formulas

IO

ZO-CO-NBN-CO-O
Ä Ä

RZ-O-CO-N-B-N-CO-O-ZR

Ä Ä

in which A is an alkyl radical, e.g. B. methyl, ethyl, allyl, also a phenyl or benzyl radical, B a polymethylene chain with preferably 2 to 10 CH ₂ groups or a phenylene radical, Z an N, N-disubstituted / I-aminoethyl radical, an N ₁ N- disubstituted o-, m- or p-aminophenyl radical or an a-, ß- or y-pyridyl radical, R a saturated or unsaturated lower aliphatic hydrocarbon radical, such as methyl, ethyl, propyl, allyl, also a cyclohexyl or benzyl radical and X an anionic radical, such as. B. J, Br, Cl Method of manufacture
of new bis-carbamic acid esters

Applicant:
Austrian nitrogen works

Corporation,
Linz / Danube (Austria)

Representative:

Dipl.-Ing. Dipl.-Chem. Dr. phil. Dr. techn. J. Reitstötter, Patent attorney, Munich 15, Haydnstr. 5

Claimed priority:
Austria from September 30, 1954

20 Dr. Otto Schmid, Leonding near Linz / Donau (Austria), has been named as the inventor

^25th

or - O SO ₃ CH ₃ or -SO ₃

C ₆ H ^

show a very strong cholinesterase inhibitory effect.

The pharmacological properties of these new compounds are partly different from those of the substances used medically up to now. For example, CH ₃ denotes 30, for example, the compound of the formula prepared according to the invention

(CH ₃ ) ₃ : N-

CO-N- (CH ₂ ) ₆ -N-CO-O- «■

• ·

CH ₃ CH ₃

-N- (CH ₃ ),

(2Y) "

In comparison with the bromomethylate of dimethyl-carbamic acid-m-dimethylamino-phenyl ester, a stronger and longer-lasting effect with lower toxicity. In addition, the muscarinic effect (effect on intestinal motor skills, saliva secretion, heart activity, etc.), which is undesirable in some applications, is significantly weaker than with neostigmine and similar compounds.
The compounds alkylated on the carbamic acid nitrogen according to the present invention are stable in aqueous solution, so that heat sterilization and storage of such substances in aqueous solution is possible without loss of effectiveness. This is of great importance for practical use.

Similar properties are also shown by 3-oxypyridine produced by the process according to the invention derived compounds, e.g. B. the formula

45

N-

-0-CO-N- (CH ₂ ) ON-CO-O-

CH ₅

CH,

CH, (2J) "

In the compound of the formula prepared according to the invention

(CH ₃ ) ₃ : N • CH ₂ • CH ₂ • O • OC • N • (CH ₂ ) _e -N-CO-O-CH ₂ • CH ₂ • N: (CH ₃ ) ₃

CH,

CH, "(2JY

709 880/418

a very strong neuromuscular effect can be observed.

To carry out the claimed manufacturing process, dicarbamic acid dichlorides are generally used formula

Cl-CO-N-B-N-CO-Cl

optionally with the addition of acid-binding substances, with oxy compounds containing a tertiary nitrogen atom the general formula

Z-OH,

expediently implemented in the form of their salts. The ditertiary compounds formed in this way can with the help of Compounds of the general formula RX are converted into the corresponding quaternary compounds. These compounds can also be obtained directly by reacting the dicarbamic acid dichlorides in general formula

Cl-Co-N-B-N-Co-Cl

A A

with a quaternary nitrogen atom containing oxy compounds of the general formula

[RZ · OH] ⁺ X "

reach, whereby acid-binding substances can also be used.

As oxy compounds containing a tertiary nitrogen atom, there are compounds of the general Formulas

(R) ₂ N • CH ₂ • CH ₂ • OH

OH

(in which R represents the same or different radicals as defined above) into consideration.

If the reaction is carried out directly with oxy compounds containing a quaternary nitrogen atom the ammonium compounds which can be derived from the tertiary oxy compounds mentioned reach the general formulas

[(R) ₃ N-CH ₂ -CH ₂ -OH] ⁺ X ".. _, OHl ⁺ X"

, 0Hl ⁺

R-N

- J

(in which R represents the same or different radicals as defined above) for use.

The dicarbamic acid dichlorides required as starting substances for the process according to the invention can can be made in different ways. So it is z. B.

possible to convert the corresponding disecondary bases into dicarbamic acid dichlorides using phosgene:

HN-B-NH + 2COCl ₂ Ä Ä ClOC -NBN- COCl + 2 HCl
Ä Ä

A synthetic route which leads via the easily accessible ditertiary bases, which compounds is particularly advantageous by means of phosgene in good yield in the following manner with the formation of the desired dicarbamic acid dichlorides be dealkylated:

YNBNY + 2COCl ₂ Ä Ä ClOC-NBN-COCl
A A

YCl

In the formulas, Y denotes a lower alkyl group, A denotes an alkyl group such as a methyl, ethyl, alkyl group or a phenyl or benzyl group and B denotes a polymethylene chain with preferably two to ten CH ₂ groups or a phenylene group.

The conversion according to the invention of the N, N'-disubstituted Dicarbamic acid dichlorides of the above formula with oxy compounds containing a tertiary or quaternary nitrogen atom is advantageous in the presence of internal ■ different solvents, such as. B. toluene or xylene, carried out; but it can also be carried out without such solvents. It is also with this reaction often useful in the presence of acid-binding substances, such as. B. tertiary amines to work. Particularly Good results can also be achieved with the alkali compounds of the oxy compounds used tertiary nitrogen, such as. B. the sodium salts of m-dimethylaminophenol or 3-oxypyridine achieved will.

The quarternization of the inventively obtainable, ditertiary bases of the general formula disubstituted on the carbamic acid nitrogen ZO-CO-N-B-N-CO-OZ

Ä Ä

surprisingly takes place at relatively very low temperatures, usually at room temperature, so that an often harmful influence of higher temperatures can be avoided and very pure products are obtained will. The quarternization is also expediently carried out in inert solvents, such as. B. Acetone, methyl ethyl ketone, methanol, ethanol or in solvent mixtures of this type carried out.

The parts given in the following examples are parts by weight.

example 1

15 parts of Ν, Ν, Ν ', Ν'-tetramethylhexamethylenediarnine are added dropwise at room temperature with stirring to 100 parts of a _{toluene solution containing 40 ° / 0} phosgene, the phosgene escaping with the chloromethyl formed through an ascending condenser being condensed in a cold trap. After completion of the dropping, the mixture is heated to 100 ° C and at this temperature

5 6

temperature while stirring the phosgene of the cold trap in the gas. After the toluene has been distilled off, the condition is passed through the reaction mixture; The crude product retained can be used for the unreacted further reaction from the reaction mixture without further purification.
softening phosgene is recently in a cold trap that consists of 19 parts Ν, Ν, Ν ', Ν'-tetramethyloctame-

condensed. The repeated passing through of the crude octamethylene-bis- (phosgene which had reached the N-reaction through the reaction mixture methyl-carbamic acid chloride) with 30 parts in xylene is continued in this way for 7 hours. After the suspended sodium salt of m-dimethylaminophenol has cooled, it is filtered and the phosgene present is reacted by stirring at 100 ° C for 4 hours. Idaren solution is distilled off with the toluene and the re-The cooled reaction product is distilled with water, with stand in vacuo. The hexamethylene bis-io 5 ° / ₀ strength sodium hydroxide solution, then again with water (N-methyl-carbamic acid chloride) is washed at one pressure and then the xylene is removed in vacuo from 0.2 mm Hg at 169 to 170 ° C as colorless, rather steamy. There are so 26 parts of octamethylene bisviscous oil over, which soon completely crystallizes. The (N-methyl-carbamic acid-m-dimethylaminophenyl ester) yield is 10.6 parts. obtain.

A solution of 11.9 parts of m-dimethylaminophenol 15 10.9 parts of octamethylene-bis- (N-methyl-carbamine in 90 parts of xylene (mixture of isomers) becomes an acid m-dimethylaminophenyl ester) in 40 parts of sodium methylate solution from 2.0 parts Na dissolved in 25 parts of benzene and, with the addition of animal charcoal, methanol was added for 1 hour; it is then distilled off, refluxed and then filtered, and the benzene is completely removed until the methanol is removed and the boiling point is distilled off. The residue is achieved in 100 parts of acetodes xylene. The residue obtained in this way, a solution of methyl bromide with a content of in which the sodium salt of m-dimethylamino-13 parts of methyl bromide is dissolved and is in solid, crystallized form in space phenol for 4 days, is allowed to stand at temperature. The precipitated crystals (9.9 parts of hexamethylene-bis- (N-methyl-carbarnic acid- are filtered off with suction, washed with acetone and chloride) added in vacuo. The reaction mixture is dried under. There are so 12.4 parts octamethylene-bis-stirring heated for 3 hours at 100 ° C, after cooling, 25 (N-methyl-carbamic acid m-diemthylaminophenylesterdreimal with water, three times with 5 ° / _o aqueous sodium hydroxide solution brommethylat) was obtained. That from a solution in ice and then washed three times with water; The product is reprecipitated with methyl ethyl ketone in vinegar, then the xylene is evaporated off in vacuo and the white, finely crystalline powder shows a molten oily residue from standing in the air from the last point of 150 to 154 ° C.
Freed residues of xylene, with the product completely 30

crystallized. There are thus 15.6 parts of hexamethylene-bis Example 3

(N-methyl-carbamic acid-m-dimethylaminophenyl ester)

obtain. By recrystallization from methanol or from the decamethylene-bis- (N-methyl-carbamic acid-m-

Acetone petroleum ether is the previously mostly slightly colored dimethylaminophenyl ester bromomethylate) Substance in the form of a white, finely crystalline powder 35 in the same way as the octamite described in Example 2 methylene-bis (N-methyl-carbamic acid-m-dimethyl) obtained with a micro-melting point of 88.5 to 90 ° C. aminophenyl ester bromomethylate). That included

33.4 parts of hexamethylene-bis (N-methyl-carbamic acid- decam-dimethylamino-phenyl ester obtained as a white, finely crystalline powder) are dissolved in 85 parts of methylene-bis (N-methyl-carbamic acid-m-dimethylamithylethyl ketone, 100 parts) absolute ethanol and 40 nophenyl ester bromomethylate) shows, added from a solution in 50 parts of iodomethyl. After standing for 4 days, glacial acetic acid is reprecipitated with methyl ethyl ketone, a micro at room temperature is melting point of 164 to 170 ° C. until the onset of cloudiness.
Methyl ethyl ketone added and left at room temperature for 8 days. The finely crystalline precipitated Pro Example 4
The product is filtered off with suction, washed with methyl ethyl ketone 45

and dried in vacuo. There are 32.6 parts of 15 parts of Ν, Ν, Ν ', Ν'-tetramethylhexamethylenediamine

Hexamethylene-bis-iN-methyl-carbamic acid-m-dimethyl are obtained with stirring in 100 parts of 35 ° / ₀ phosgene entaminophenyl ester iodomethylate). Added dropwise by further holding toluene solution and the addition of methyl ethyl ketone in the reaction is kept even more of the mixture for 6 hours at 100 ° C., the equivalent substance being obtained. It can be condensed by falling over 50 softening, unreacted phosgene and purified again and again in gaseous form from a solution in absolute ethanol with methylethyl- ketone through the reaction mixture and provides a white, finely crystalline is passed. After standing for 12 hours at room powder with a micromelting point of 138 to 139.5 ° C, the temperature is filtered; of the clear toluene solution. 60 parts are distilled off and added to the remaining

By quaternizing the hexamethylene bis (N- 55 toluene solution of the hexamethylene bis (N-methyl-carbmethyl-carbamic acid-m-dimethylaminophenyl ester) with amino acid chloride) 40 parts of ß-dimethylaminoethanol other alkylating agents, such as. B. an ethyl halo added, with a precipitation entgenid when heated, Allyl halide or benzyl halide are the result. After standing at room temperature for 12 hours speaking bisquaternary compounds available. The hygroscopic crystals (hydrolightest the iodides and bromides react, so 60 chloride of dimethylaminoethanol) is separated. the that the quaternary compounds are already at room temperature solution in vacuo by gentle heating temperature can be produced. In the case of the chlorides, toluene is often freed and the residue obtained is used Heating is necessary to ensure long reaction times when removing the excess dimethylaminoethanol Avoid quartering. 1 week in a dish in a vacuum over concentrated

65 trated sulfuric acid left to stand. In this way

Example 2 are 21 parts of hexamethylene bis (N-methyl-carbamine-

acid dimethylaminoethyl ester) as practically odor in the same way as the loose oil described in Example 1 was obtained.

Hexamethylene-bis-iN-methyl-carbamic acid chloride) is 21 parts of the hexamethylene-bis-

octamethylene bis (N-methyl-carbamic acid chloride) 70 (N - methyl - carbamic acid - dimethylaminoethyl ester)

7 8

are dissolved in 125 parts of acetone and 40 parts of methyl ketone reprecipitated, 9.4 parts with a micro-

iodide added. Reaction occurs when heated; melting point of 100 to 103 ° C can be obtained,

fine white crystals soon separate out, which after. .

12 hours of standing at room temperature, example

washed with acetone and dried. It 5 4.7 parts of hexamethylene bis (N-methyl-carbamic acid-

so 35.3 parts of hexamethylene bis (N-methyl-m-dimethyl-aminophenyl ester) are in 40 parts

carbamic acid choline iodide ester) obtained, which dissolved after the methyl ethyl ketone and this solution with 3.15 parts

Acetone dimethyl sulfate was added to precipitate from a solution in methanol. After standing for several hours

exhibit a micro-melting point of 169-171 ° C. the hexamethylene formed falls at room temperature

i ° bis (N-methyl-carbamic acid-m-dimethyl-aminophenyl-

Example 5 ester methosulfate) as a thick oil.

- • 2 parts of sodium are dissolved in 24 parts of methanol, Example 8

to the sodium methylate solution formed 8.25 parts 4.7 parts of hexamethylene-bis (N-methyl-carbamic acid-

3-Oxy-pyridine and 90 parts of xylene (mixture of isomers) ¹ S ( m-dimethyl-aminophenyl ester) are added in 40 parts. Methyl ethyl ketone is now dissolved under nitrogen as a protective gas and this solution is distilled off with 6.3 parts until the boiling point of the xylene ethyl iodide is added. After standing for several days at reached and all the methanol has been removed. The 25 to 30 ° C can be the hexamethylene-bis-residue formed is iodoethylate with a solution of 11.7 parts (N-methyl-carbamic acid-m-dimethyl-aminophenyl ester-hexamethylene-bis- (N-methyl-carbamic acid chloride) ²⁰ ) ) with 45 parts of xylene customary for such quaternary products and, with vigorous stirring, precipitants, such as. B. benzene, precipitate. Maintained at 80 ° C for 4 hours.

After cooling, three times with water, three times example y

5 ° / _o aqueous sodium hydroxide solution and then three times with 5.0 parts of octamethylene-bis- (N-methyl-carbamic acid

Water washed. The xylene solution is sodium ^2-dimethyl-5 m aminophenylester) sulfate in 35 parts dried and the xylene in vacuo, dissolved completely methyl ethyl ketone. This solution is distilled off with a. This gives 11.0 parts of hexamethylene solution of 3.8 parts of methyl p-toluenesulfate in bis- (N-methyl-carbamic acid-3-pyridyl ester). 20 parts of methyl ethyl ketone are added and the reaction

6 parts of hexamethylene-bis- (N-methyl-carbarnic acid mixture kept for 9 hours at 60 ° C. The octamethylene-3-pyridyl ester) are dissolved in 8 parts of acetone and 3 ° bis-iN-methyl-carbamic acid-m-dimethyl-aminophenyldiese Solution mixed with 10 parts of iodomethyl, whereupon ester-p-toluenesulfonate) precipitates as a thick oil. is allowed to stand at room temperature. As soon as the

The reaction is complete, the crystalline application of m-dimethylaminophenols can be extracted from hexamethylene-bis-iN-methyl-carbamic acid-S-pyridyl with a similar result, equimolecular amounts of ester-iodomethylate), washed with acetone 35 o-dialkylaminophenols or p- Dialkylaminophenols and dried. The crude product obtained in this way is made from or also used other m-dialkylaminophenols. 24 parts of 96 ° store ethanol redissolved and 7.5 parts are redissolved in the process. Examples include: m-diethylhexamethylene-bis (N-methyl-carbamic acid-3-pyridylaminophenol, m-dipropylaminophenol, m-diisobutyl ester iodomethylate) with a melting point of 152 bis aminophenol, m-di-n-butylaminophenol obtained m-methyl-157 ° C. 4 ° ethyl-aminophenol and the corresponding o- or

7.3 parts of hexamethylene bis (N-methyl-carbamic acid-p-dialkylaminophenols, also dicyclohexylaminophe-3-pyridyl ester) are dissolved in 120 parts of acetone, with nols, dibenzylaminophenols and similar compounds. 22 parts of methyl bromide are added and to completion. _

the reaction left to stand at room temperature, with example

Crystals fall out. The extracted and dried 45 in the same way as described in Example 1 is -Reaction material (9.9 parts) can be quaternized by dissolving hexamethylene-bis- (N-methyl- and cases are cleaned with methyl ethyl ketone. The carbamic acid m-diniethyl aminophenyl ester) with bromine -Hexamethylene-bis- (N-methyl-carbamic acid-3-pyridyl-methyl instead of iodomethyl the hexamethylene-bisester-bromomethylate) shows a micro-melting point of (N-methyl-carbamic acid-m-dimethyl-aminophenyl-147 up to 150 ° C. 50 ester bromomethylate). After cleaning through

Dissolving in glacial acetic acid and precipitating with methyl ethyl ketone shows Example 6 the substance has a micro-melting point of 170 to

173 ° C.

■ The substance is prepared in a manner analogous to the previous example 11

Example for the hexamethylene-bis- (N-methyl- 55

carbamic acid 3-pyridyl ester) described, under 24.0 parts of hexamethylene bis (N-methyl-carbamine-

application of decamethylene bis (N-methyl-carbamic acid chloride) and 36.8 parts of choline iodide are acid chloride) instead of hexamethylene-bis- (N-methyl- smaller, mixed well and then in vacuo for 7 hours ■ cafbamic acid chloride) produced. It is kept at 105 to 110 ° C.

Share decamethylene-bis- (N-methyl-carbamic acid- 60 The molar ratio hexamethylene-bis- (N-methyl- ■ chloride) 10.1 parts of decamethylene bis (N-methyl-carbcarbamic acid chloride) to choline iodide is 1: 1.78. amic acid 3-pyridyl ester). After a while, the reaction mixture begins to close

13.1 parts of decamethylene-bis- (N-methyl-carbamic acid melt and gaseous strongly. The melt solidifies • 3-pyridyl esters) become porous in 8 parts of absolute ethyl but after a few hours again alcohol and 200 parts of acetone dissolved, this solution with 65 mass. After cooling, the reaction product is Parts of methyl bromide are added and the mixture is triturated with 100 parts of acetone at room temperature, filtered off with suction, with acetone rature left. When the reaction has ended, it is washed and dried in vacuo. One receives on the crystalline precipitated decamethylene-bis- (N-methyl- this way 46.7 parts in acetone insoluble substance. carbamic acid 3-pyridyl ester bromomethylate) from a This product is crystallized from 750 parts of n-buta mixture of absolute ethyl alcohol and methylethyl- 70 nol, whereby a pale yellow colored hexa-

methylene - bis - (N - methyl - carbamic acid - β - dimethylaminoethyl ester iodomethylate) in an amount of 37.4 parts, that is 80% of the amount of crude product used or 71% of theory, calculated on the choline iodide used. The product melts from 161 to 170 ° C. By recrystallizing this product again from 60 parts of methanol and 240 parts of acetone, 26.2 parts of a pure, white hexamethylene bis (N-methyl-carbamic acid / 5-dimethylaminoethyl ester iodomethylate are obtained ). The substance * ° melts at 169.5 ° C.

Claims (2)

Patent claims: 1. Process for the preparation of new bis-carbamic acid esters of the general formulas Z-O-CO-N-B-N-CO-O-Z or RZ · O · CO · N · B · N · CO · O · ZRl ⁺⁺ 2 X 25th in which A is an alkyl radical, a phenyl or benzyl radical, B is a polymethylene chain with preferably 2 to 10 CH ₂ groups or a phenylene radical, Z is a Ν, Ν-disubstituted / 3-aminoethyl radical, a Ν, Ν-disubstituted o-, m - or p-aminophenyl radical or an α-, β- or y-pyridyl radical, R a saturated or unsaturated lower aliphatic carbon hydrogen radical, a cyclohexyl or benzyl radical and X is an anionic radical, thereby characterized in that one dicarbamic acid dichlorides of the general formula Cl-CO-N-B-N-CO-Cl 1 with oxy compounds of the general formula containing a tertiary nitrogen atom Z-OH expediently in the form of their salts, optionally with the addition of acid-binding substances, and optionally the ditertiary compounds formed in this way with compounds of the general formula RX quaternized (where A, B, Z and R have the meanings given above). 2. The method according to claim 1, characterized in that the dicarbamic acid dichlorides general formula Cl-CO-N-B-N-CO-Cl with a quaternary nitrogen atom containing oxy compounds of the general formula [RZ-OH] ⁺ X ^ (where A, B, Z and R have the meanings given above), optionally with the addition of acid-binding agents Substances. © 709 8S0 / 418 2.