US3901937A - Quaternary carbamates - Google Patents

Quaternary carbamates Download PDF

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US3901937A
US3901937A US63869467A US3901937A US 3901937 A US3901937 A US 3901937A US 63869467 A US63869467 A US 63869467A US 3901937 A US3901937 A US 3901937A
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quaternary
dimethylcarbamoxyphenoxy
dimethylamino
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dimethiodide
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Harold Z Sommer
John Krenzer
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US Secretary of Army
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US Secretary of Army
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06Esters of carbamic acids

Abstract

New chemical compounds having the generic formula:

WHEREIN N IS AN INTEGER SELECTED FROM 2-7 INCLUSIVE AND WHEREIN X is one equivalent of an anion selected from the group consisting of monovalent and polyvalent anions, and having utility as incapacitating agents and in munitions.

Description

United States Patent [191 Sommer et a].

[ 1 Aug. 26, 1975 QUATERNARY CARBAMATES [75] Inventors: Harold Z. Sommer, Havre De Grace, Md.; John Krenzer, Chicago, Ill.

[73] Assignee: The United States of America as represented by the Secretary of the Army, Washington, DC.

[22] Filed: May 8, 1967 [2]] Appl. No.: 638,694

[52] US. Cl 260/482 C; 260/999; 424/300 [51] Int. Cl. C07C 125/00 [58] Field of Search 260/482 C; 167/46 A, 47;

[56] References Cited UNlTED STATES PATENTS 5/1965 Brown 102/24 l/l968 Mayer et al 260/482 C Primary ExaminerLeland A. Sebastian Attorney, Agent, or Firm-Nathan Edelberg; Robert P. Gibson; Robert W. Church 5 7 ABSTRACT New chemical compounds having the generic formula:

3 Claims, N0 Drawings QUATERNARY CARBAMATES This invention relates to the synthesis of new toxic chemical compounds which are useful as chemical warfare agents. More particularly, our invention is concerned with novel compounds produced by means of a quaternizing reaction.

The chemical agents act mostly on the peripheral cholinergic nervous system which includes the motor nerves, the preganglionic fibers, the ganglia, the postganglionic parasympathetic fibers, and neuromuscular functions. The transmission of impulses along a nerve or from nerve fibers to muscle fibers or secretory cells or from one nerve fiber to another across synapses in ganglia is thought to involve chemical changes either directly or as the source of potential differences.

Quaternary ammonium compounds in general are known to be physiologically active materials. Mainly because of their positively charged onium centers they are attracted by anionic sites in animal tissues, particularly those situated at cell surfaces and interfaces. They can induce physiological responses that mimic or antagonize the action of acetylcholine as a result of their interaction with the various physiological receptor sites of acetylcholine, especially those at membranes of muscle cells. They also combine with enzymes such as acetylcholinesterase, other esterases, acetylcholineacetylase, etc., thus inhibiting their participation in the biological processes.

One of the significant anatomical differences between the neuromuscular junctions and other acetylcholine receptive sites is the absence of a membrane barrier or a sheath such as envelops the ganglia. The comparative ease of accessibility of the neuromuscular junctions to onium compounds contributes to their relatively fast onset of action and partly explains why in many instances relatively small doses suffice to evoke physiological actions that modify or interrupt normal neuromuscular impulse transmission.

Depending on their chemical structures different quaternary compounds interfere with the mechanism of impulse transmission in different manners and the final physiological effects can vary considerably. Some quaternary ammonium compounds are used as therapeutic agents, others are known to be lethal. The magnitude, accessibility, and distribution of the positive charges in quaternary compounds are belived to be the key factors in the determination of specificity of action. Recognition of these facts explains the strikingly different physiological behavior so often observed when structurally very closely related compounds are compared. The nature of the groups attached to the quaternary nitrogen influences the distribution of the cationic charges. The length and branching of aliphatic chains and the volume and configuration of aromatic and alicyclic rings have a bearing on the ease or difficulty of approach to the specific receptor sites. Electrophilic and nucleophilic centers in the molecule will insert their inductive effects on the positive charges and can also aid in the interaction with the esteratic sites of various enzymes. These sites are believed to be located in close vicinity t the anionic s'ites' of the active centers. Substitution of different functional groups influence association and hydration andmay considerably change the solubilities in physiological media. In bisquaternary and poly-quaternary compounds, the distance between the electric charges must be considered.

These factors contribute to governing the rate and reversibility of the chemical reactions involved, and which determine the final physiological responses.

Our chemical agents interfere with the normal process of neuromuscular impulse transmission and thus disrupt the propagation of impulses from nerves to muscles. We have also found these compounds to be extremely toxic at relatively low dose levels in various animals.

The object of this invention is to synthesize new lethal agents useful in chemical warfare in high yields wherein said products are well suited for industrial scale manufacture.

Other objects of and uses for the invention will be obvious from the following detailed description.

Our compounds may be employed in any munition suitable for handling a relatively non-volatile toxic agent such as bombs, shells, spray tanks, rockets, missiles, aerosol generators, and others.

In accordance with our invention a mixture of 3- nitro-S-dimethylcarbamoxyphenyl, an a-(4- nitrophenoxy )-w-bromoalkane, and potassium carbonate in a solvent such as dimethylformamide was heated on a steam bath for 6 hours. The reaction mixture was poured into cold water. The oily material that separated was collected and on standing at room temperature became solid. Recrystallization from ethanol yielded the pure intermediate, a-(4-nitrophenoxy)-m- (3-nitro-5-dimethylcarbamoxyphenoxy)alkane. This dinitrocompound was catalytically hydrogenated under pressure. After the hydrogenation was completed, the catalyst was removed by filtration and the solvent removed under reduced pressure. A crystalline residue, a-( 4-aminophenoxy)-w-( 3-amino-5 dimethylcarbamoxyphenoxy)alkane was obtained. The diaminointermediate without further purification was dissolved in dimethylformamide and an excess of iodide was added. After allowing the solution to stand at room temperature for a few minutes, the organic base, 2,6-lutidine, was mixed in. After an additional few minutes, the same portion of 2,6-lutidine was again added. After an interval of 2 hours a solvent such as acetone was added and the mixture was left standing at room temperature for 2 days. The crystalline product, an a-4-dimethylaminophenoxy)-w-(3-dimethylamino-5- dimethylcarbamoxyphenoxy) alkane, that separated was collected on a filter and washed successively with acetone, ethyl acetate, and ether, and finally dried.

The new compounds of our invention, bis-quaternary carbamates, may be represented by the following generic. formula: I

@i G m- 0 l I H -CH H3 7 Where n is an integerselected from 27 inclusive and where X is one equivalent of an anion selected from monovalent and polyvalent anions. Y

The procedure used for the preparation of the new toxic materials is schematically shown as follows:

is Y Q'Q-( HQ -O Qty-CH ion exchange H3C /N CH3 CH3 C 3. 1 l

.. I O -l zl f'g g a H 'cu cH U H3 3 Xe v . EXAMPLE A mixtureof 3-nitro-5 dimethylcarbamoxyphenol (4 g.),.1-(4-nitrophenoxy)-2-bromoethane (4.6 g.), and potassium carbonate (2.5 g.) in ml of dimethylformamide was heated on a steam bath for 6 hours. The reaction mixture was then poured into cold water. The oily material that separated was collected and on standing at room temperature for about 2 hours became crystalline. Two recrystallizations from ethanol yielded the pure intermediate, 1-(4-nitrophenoxy)-2-(3-nitro- 5-dirnethylcarbamoxyphenoxy)ethane, (1.5 g.), m.p. 1091 l 1C.

Anal. Calcd. for c yHnNgogi C, H, N, 10.7. Found: C, 52.2; H, 4.5; N, 10.8.

The above dinitro-compound (0.7 g.) in ml. of tetrahydrofuran was hydrogenated catalytically at 3 atm. and with 5% of Pt on charcoal. After the hydrogenation was completed, the catalyst was removed by filtration amide and 6 ml. ,o'f'rnethyl iodide was added. The mixture was stirred at room temperature for 15 minutes.

Following this, 0.41 ml. of 2,6-lutidine was added and stirring was continued for additional 15 minutes. A second 0.41 ml. portion of 2,6-lutidine was added and stirring was continued for 2 hours. Then, 25 ml. of acetone was added and the mixture allowed to stand at room temperature for 2 days. The crystalline material that separated was filtered and washed successively with acetone, ethyl acetate, and ether. After drying the pale yellow material (0.84 g.) in vacuo (about 1 mm.) over phosphorous p'entoxide, the product, 1-(4- .diinethylaminophenoxy)-2-(3-dimethylamino-5- dimethylcarbamoxyphenoxy)ethane dimethiodide, was obtained which melted at 132C.

Anal. Calcd. for C H I N O H O: C, 40.6; H, 5.4; O, 10.6. Foundi C, 40.5; H, 5.9; O, 10.9.

Toxicity Intravenous LD Rabbits Mice 0.007 mg/kg 0.016 mg/kg The compounds which are generically described above and that are representativeof our invention are listed belowby name:

l-(4-Dimethylaminophenoxy)-2-(3 dimethylamino- 5-dimethylcarbamoxyphenoxy)ethane dimethiodide.

l-( 4-Dimethylaminophenoxy )-3-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)propane dimethiodide.

l-( 4-Dimethylaminophenoxy )-4-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)butane dimethiodide.

l-(4-Dimethylaminophenoxy )-5-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)pentane dimethiodide.

l-(4-Dimethylaminophenoxy)-6-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)hexane dimethiodide.

l-( 4-Dimethylaminophenoxy)-7-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)heptane dimethiodide.

We have shown a preferred compound in which the anion is limited to the halogen moiety, in particular the iodide, since methyl iodide is readily available and is a good quaternizing agent. In general, however, it is only necessary that the anions merely have to meet the requirement of being capable of forming a stable salt with the quaternary nitrogen. Thus, the halogen ions can be exchanged with other anions of a relatively strong acid selected from monovalent and polyvalent by conventional methods. For example, if X is an iodide in the final product, a solution of the compound can be treated with a basic ion exchange resin or mixed with silver oxide and subsequently the desired acid is added to the quaternary hydroxide solution. Anions may also be supplied by metathesis with the halide form of the quaternary ammonium compound. Also, suitable as representations of X are the anions hydrogen oxalate, perchlorate, hydrogen sulfate, and tetraphenylboronate. Representative examples of these additional monovalent and polyvalent end products are:

1-( 4-Dimethylaminophenoxy )-2-( 3-dimethylamino- 5-dimethylcarbamoxyphenoxy)ethane dimethohydrogenoxalate.

wherein n is an integer selected from 2-7 inclusive and wherein X is one equivalent of an anion selected from the group consisting of monovalent and polyvalent anions, said anions being selected from the group consisting of halide, hydrogen oxalate, perchlorate, hydrogen sulfate, and tetraphenylboronate.

2. New chemical compound having the name 1-(4- dimethylaminophenoxy)-2-(3-dimethylamino-5- dimethylcarbamoxyphenoxy)ethane dimethiodide.

3. New chemical compound having the name 1-(4- dimethylaminophenoxyl)-3-(3-dimethylamino-5- dimethylcarbamoxyphenoxy) propane dimethiodide.

Claims (3)

1. NEW CHEMICAL COMPOUNDS HAVING THE GENERIC FORMULA:
2. New chemical compound having the name 1-(4-dimethylaminophenoxy)-2-(3-dimethylamino-5 -dimethylcarbamoxyphenoxy)ethane dimethiodide.
3. New chemical compound having the name 1-(4-dimethylaminophenoxyl)-3-(3-dimethylamino-5-dimethylcarbamoxyphenoxy) propane dimethiodide.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3188955A (en) * 1961-03-31 1965-06-15 Western Co Of North America Explosive charge assemblies
US3365484A (en) * 1965-05-10 1968-01-23 Velsicol Chemical Corp Alkyl benzhydrylcarbamates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3188955A (en) * 1961-03-31 1965-06-15 Western Co Of North America Explosive charge assemblies
US3365484A (en) * 1965-05-10 1968-01-23 Velsicol Chemical Corp Alkyl benzhydrylcarbamates

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