US3919289A - Carbamates - Google Patents

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US3919289A
US3919289A US63869567A US3919289A US 3919289 A US3919289 A US 3919289A US 63869567 A US63869567 A US 63869567A US 3919289 A US3919289 A US 3919289A
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dimethylaminophenoxy
dimethylcarbamoxy
nitrophenoxy
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propane
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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
    • C06EXPLOSIVES; MATCHES
    • C06DMEANS FOR GENERATING SMOKE OR MIST; GAS-ATTACK COMPOSITIONS; GENERATION OF GAS FOR BLASTING OR PROPULSION (CHEMICAL PART)
    • C06D7/00Compositions for gas-attacks

Abstract

New chemical compound having the generic formula:

wherein n is 2-8 methylene groups and X is one equivalent of an anion selected from the group of monovalent and polyvalent anions, and having utility as an incapacitating agent and in munitions.

Description

United States Patent Sommer et a1.

1 5] Nov. 11, 1975 41 CARBAMATES [75] Inventors: Harold Z. Sommer, Havre de Grace.

Md; John Krenzer, Chicago, 111. [73] Assignee: The United States of America as represented by the Secretary of the Army, Washington, DC.

[22] Filed: May 8, 1967 [21] Appl. No.: 638,695

[52] US. Cl. 260/479 C; 424/300 [51] Int. Cl. C07C 125/00 [58] Field of Search .v 260/482 C, 479 C; 167/46 A, 47; 424/300 [56] References Cited UNITED STATES PATENTS 2,812,247 11/1957 Gysin et a1. 260/482 UX 3.188.955 6/1965 Brown 102/24 Primary Emminer-Leland A. Sebastian Atmrney. Agent, or Firm-Nathan Edelberg; Robert P. Gibson; Kenneth P. Van Wyck [57] ABSTRACT New chemical compound having the generic formula:

wherein n is 2-8 methylene groups and X is one equivalent of an anion selected from the group of monovalent and polyvalent anions. and having utility as an incapacitating agent and in munitions.

2 Claims, No Drawings 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 inter faces. 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 believed 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 nitrogens 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 to the anionic sites of the active centers. Substitution of different functional groups influence association and hydration and may considerably change the solubilities in physiological media. In bis-quaternary and polyquaternary compounds, the distance between the electric charges must be considered.

2 These factors and others govern the rate and reversibility of the chemical reactions involved, that 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.

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.

Other objects of and uses for the invention will in part be obvious and will in part appear hereinafter in the following detailed description thereof.

In accordance with our invention, a mixture of 4- acetoxy-2-nitrophenol, an a-halo-w-(4-nitrophenoxy- )alkane, potassium carbonate, and a solvent such as dimethylformamide was heated on a steam bath for a few hours and then cooled. The addition of water precipitated an oz-(4-acetoxy-2-nitrophenoxy)-w-(4-nitrophenoxy)alkane. Upon hydrolysis with hydrochloric acid and under reflux conditions in a solvent such as ethanol for a few hours an a-(4-hydroxy-2-nitrophenoxy)-w-(4-nitrophenoxy)alkane resulted. The hydroxy group was carbamylated by refluxing a mixture of the said a(4-hydroxy-2-nitrophenoxy)-m-(4-nitrophenoxy)alkane, dimethyl carbamoyl chloride, and pyridine for one hour. After the mixture cooled to room temperature, it was poured into ice water. The solid, an a-(4-dimethylcarbamoxy-Z-nitrophenoxy)-w- (4-nitrophenoxy)alkane, was separated by filtration. The desired quaternary a-(4-dimethylcarbamoxy-2- dimethylaminophenoxy )-w-( 4-dimethylaminophenoxy- )alkane di-methosalts were prepared by hydrogenating the above a-(4-dimethylcarbamoxy-2-nitrophenoxy)- m-(4-nitrophenoxy)alkane in a solvent such as tetrahydrofuran in the presence of a catalyst such as 5% Pt. by weight on charcoal. After the theoretical amount of hydrogen was taken up the catalyst was removed by filtration and the solvent by evaporation. The remaining oily material was dissolved in a solvent such as dimethylformamide and methyl iodide was added. After stirring the mixture for 15 minutes at room temperature 2,6- lutidine was added. After additional stirring for 15 minutes, more 2,6-lutidine was added and stirring continued for an additional two hours. The product that formed, an a-(4'dimethylcarbamoxy-2-dimethylaminophenoxy -w-( 4-dimethylaminophenoxy )alkane dimethiodide, was collected on a filter and dried. The diiodide was converted to the dihydrogenoxalate salt by passing an aqueous solution of the diiodide through a basic ion exchange resin into an aqueous acid solution such as oxalic acid. After the water was evaporated under reduced pressure, the residue was stirred with ethyl acetate and actone and recrystallized from a solvent mixture such as ethanol-ethylacetate to obtain an a-( 4-dimethylcarbamoxy-Z-dimethylaminophenoxy w-(4-dimethylaminophenoxy)alkane di (hydrogen methoxalate).

The new compounds of our invention may be presented by the following generic formula:

H I u (CHQ)2NCO O-(CHgh-O llQCl-l H=CNCH3 where n is 2-8 methylene groups and X is one equiva- A mixture of 4-acetoxy-2-nitrophenol (4g),1-bromolent of a monovalent or polyvalent anion. 3-(4-nitrophenoxy)propane (5.3g), potassium carbon- The procedure used for the preparation of the new ate (2.8g), and dimethylformamide (10ml) was heated toxic materials is schematically shown as follows: on a steam bath for 2 hours and then cooled. The addiwhere n is 2-8 methylene groups and X is one equivalent of a monovalent or polyvalent anion. 60

If compounds are desired in which X is other than a halide ion, the above quaternary compounds are treated with the desired acid by simple exchange reaction of water precipitated the product, which was retion as set forth below. moved by filtration. The crude material was recrystal- EXAMPLE from ethanol The yield was 5g mp Preparation of 1-(4-acetoxy-2-nitrophenoxy)-3-(4- Anal. Calcd. for C H MO C, 54.25; H, 4.3; O,

nitrophenoxy)propane. 34.0. Found: C, 53.9; H, 4.6; O, 33.7.

Preparation of l-( 4-hydroxy-2-nitrophenoxy)-3-(4-nitrophenoxy) propane.

A solution of l-(4-acetoxy-2-nitrophenoxy)-3-(4- nitrophenoxy)propane (0.5g) and concentrated hydrochloric acid (0.5ml) in ml of ethanol was refluxed for 4 hours and then cooled. The crystals that formed were removed by filtration and washed with cool ethanol. The dried product (0.4g) melted at l6l-l64C.

Anal. Calcd. for C, H .,N O-,: C, 53.89; H, 4.22; O, 33.52. Found: C, 53.7; H, 4.5; O, 33.6.

Preparation of l -(4-dimethylcarbamoxy- Z-nitrophenoxy )-3-( 4-nitrophenoxy) propane.

A mixture of l-(4-hydroxy-2-nitrophenoxy)-3-(4- nitrophenoxy) propane (l.0g), dimethylcarbamoyl chloride (043g), and pyridine (l0ml) was refluxed for l hour, then cooled and poured into 50ml of ice water. The solid that formed was removed by filtration and recrystallized from ethanol. The yield was 0.9g, m.p. 9294C.

Anal. Calcd. for C H N O C, 53.33; H, 4.72; N, 10.35. Found: C, 53.0; H, 5.0; N, 10.7.

Preparation of l-( 4-dimethylcarbamoxy- Z-dimethylaminophenoxy 3-(4-dimethylaminophenoxy)propane di(hydrogen methoxalate).

l-(4-dimethylcarbamoxy-Z-nitrophenoxy)-3-(4- nitrophenoxy) propane (1.0g) was dissolved in 25ml of tetrahydrofuran and hydrogenated, using 0.l g of 5% Pt/C as the catalyst. After the theoretical amount of hydrogen was taken up, the catalyst was removed by filtration, and the solvent removed under reduced pressure. The oily residue was dissolved in 5ml of dimethylformamide and 5ml of methyl iodide was added. The mixture was stirred at room temperature for IS minutes. 2,6-Lutidine (062ml) was then added and stirring was continued for minutes. A second portion of 2,6- lutidine (062ml) was added and stirring was continued for an additional hour. After addition of ml of acetone and continuous stirring for two hours, the crude solid material (1.55g), m.p. l76-l82 that formed was collected on a filter. The crude diiodide 1.3g) was dissolved in 40ml of distilled water and was passed through a column of basic ion exchange resin into an Erlenmeyer containing oxalic acid (lg). The column was rinsed by passing 20ml of distilled water through the resin. The combined eluants were evaported under reduced pressure. The excess of oxalic acid was removed from the oily residue by stirring the residue successively with ethyl acetate and acetone. After allowing the oily residue to stand in a few ml of acetone for 2 days at room temperature, it crystallized. The crude product was twice recrystallized from ethanol-ethyl acetate. The yield was 0.8g, m.p. l65-l67.

Anal. Calcd. for C H N O: C, 55.15; H, 6.45; O, 3L5. Found: C, 54.6; H, 6.8; O, 31.7.

Toxicity Intravenous LD R abhits 0.050 mg/kg Mice 0.044 mg/kg 1-(4-dimethylcarbamo xy-Z-dimethylaminophenoxy 3-( 4-dimethylaminoph enoxy )propane 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 quatemizing agent. In general, however, it is only requirement that the anions merely have to meet the requuirement of being capable of forming a stable salt with quaternary nitrogen. Thus, the halogen ions can be exchanged with other anions of a relatively strong monovalent or polyvalent acid by conventional methods. For example, ifX 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 other than the halogens may also be obtained by methathesis with the halide form of the quaternary ammonium compound. Suitable or representations of X are the anions hydrogen oxalate, perchlorate, hydrogen sulfate, nitrate, and tetraphenylboronate. Representative examples of these additional products are:

I 4-dimethylcarbamoxy-2-dimethylaminophenoxy )-3-(4-dimethylaminophenoxy)propane di( hydrogen methoxalate).

l-( 4-dimethylcarbamoxy-2-dimethylaminophenoxy)-3-(4-dimethylaminophenoxy)propane dimethoperchlorate.

l-(4-dimethylcarbamoxy-Z-dimethylaminophenoxy)-3-(4-dimethylaminophenoxy )propane dimethonitrate.

l-( 4 -dimethylcarbamoxy-2-dimethylaminophenoxy )-3-(4-dimethylaminophenoxy)propane di(hydrogen methosulfate).

l 4-dimethylcarbamoxy-Z-dimethylaminophe noxy)-3-(4-dimethylaminophenoxy )propane dimethotetraphenylboronate. We claim: 1. New chemical compounds having the generic formula:

H CH (CH,),N- -O -O(CH,)--Q:+CH,

mc-rr-cn,

wherein n is 2-8 methylene groups and X is one equivalent of an anion selected from the group of monovalent and polyvalent anions, said anions being selected from the group consisting of halide, hydrogen oxalate, perchlorate, nitrate, hydrogen sulfate, and tetraphenylboronate.

2. New chemical compounds selected from the group of compounds having the name l-(4-dimethylcarbamoxy-Z -dimethylaminophenoxy )-2 4-dimethylaminophenoxy)ethane dimethiodide, 1-(4-dimethylcarbamoxy-Z-dimethylaminophenoxy)-3-(4-dimethylaminophenoxy)propane di(hydrogen methoxalate), 1-( 4-dimethylcarbamoxy-2 -dimethylaminophenoxy )-4-( 4-dimethylaminophenoxy )butane dimethiodide, and l- 4-dimethylcarbamoxy-2-dimethylaminophenoxy)-8-(4-dimethylaminophenoxy )octane dimethiodide.

Claims (2)

1. NEW CHEMICAL COMPOUNDS HAVING THE GENERIC FORMULA:
2. New chemical compounds selected from the group of compounds having the name 1-(4-dimethylcarbamoxy-2-dimethylaminophenoxy)-2-(4 -dimethylaminophenoxy)ethane dimethiodide, 1-(4-dimethylcarbamoxy-2-dimethylaminophenoxy)-3-(4 -dimethylaminophenoxy)propane di(hydrogen methoxalate), 1-(4-dimethylcarbamoxy-2-dimethylaminophenoxy)-4-(4 -dimethylaminophenoxy)butane dimethiodide, and 1-(4-dimethylcarbamoxy-2-dimethylaminophenoxy)-8-(4 -dimethylaminophenoxy)octane dimethiodide.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2812247A (en) * 1953-09-02 1957-11-05 Geigy Ag J R Compositions and methods for influencing the growth of plants
US3188955A (en) * 1961-03-31 1965-06-15 Western Co Of North America Explosive charge assemblies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2812247A (en) * 1953-09-02 1957-11-05 Geigy Ag J R Compositions and methods for influencing the growth of plants
US3188955A (en) * 1961-03-31 1965-06-15 Western Co Of North America Explosive charge assemblies

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