US3209032A - Process for producing chloralkyl hydrazinium chlorides - Google Patents

Description

United States Patent 3,209,032 PROCESS FOR PRODUCING CHLORALKYL HYDRAZINIUM CHLORIDES Charles D. Helm, Luce Creek Drive, Annapolis, Md. No Drawing. Filed Jan. 3, 1962, Ser. No. 164,155

Claims. (Cl. 260-583) This invention is concerned with a novel group of nitrogen mustard derivatives. In one specific aspect, this invention is concerned with a method for the preparation of a novel group of nitrogen mustard derivatives.

Nitrogen mustards are tertiary amines containing at least two 2-chloroethyl groups and are the nitrogen analogs of mustard gas; these compounds have the formula in which R is an alkyl radical having from 1-4 carbon atoms. Nitrogen mustard and its derivatives have been regularly used as cancer treating agents. They have been used clinically in the treatment of neoplasms of lymphoid tissues and in the treatment of Hodgkins disease, lymphosarcoma and leukemia. However, they sulfer from the disadvantage of high toxicity, since they have a strong local vesicant action and readily penetrate human skin. As well, continued exposure to low concentrations of these substances causes opacity of the cornea of the eye.

It is an object of this invention to provide materials, similar in structure and properties to the nitrogen mustards but having considerably lower toxicity. Further objects will be set forth in the description of the invention.

I have found that a decrease in toxicity can be achieved by tying up the amino group in the nitrogen mustard molecule by a hydrazinium linkage. This is achieved by chloraminating the amino group to yield a hydrazinium chloride. This change gives rise to pounds, the chloralkyl hydrazinium chlorides. compounds have the formula in which R is an alkyl radical having from 1 to 4 carbon atoms or a third 2-chloroethyl group.

If chloramination of methyldichloroethylamine is attempted by any of the known techniques, cyclization of the amine (reaction 1) occurs rather than chloramination and a brown, gummy mass is obtained which contains only a small amount of the desired product.

These I have developed a method by which it is possible to avoid this cyclization and to carry out chloramination to For example, a standard draziniums is shown in a new group of comthe desired hydrazinium chloride. This method is based NH: N112 in which R is an alkyl radical having from 1 to 4 carbon atoms.

The chloramine used by my procedure can be made by the standard reaction of ammonia and chlorine in the gas phase in accordance with the teachings of Sisler [Sisler et al., JACS, 76, 3096 (1954)]. A generator may be constructed in accordance with the teachings of Sisler et al., to provide a continuous stream consisting essentially of chloramine and excess ammonia, the latter being present in a ratio of 5 parts ammonia to one part chloramine to prevent undesirable side reactions. As Well, nitrogen may be present as a diluent in the gaseous mixture.

N-alkyl-2,2-dihydroxydiethylamine is dissolved warm 2-propanol. The quantity of propanol used and the temperature to which it is heated depends upon the solubility of the particular amine being used bearing in mind that as always, too much excess solvent is inconvenient. I have found that successful temperature can be anywhere in the range of between 35 and 60 C. The solution is then cooled to room temperature and treated with gaseous chloramine by known technique, one of which is set forth by Omietanski (US. Patent 2,955,108). It is important to maintain the reaction at room temperature, since although chloramine is thermodynamically stable up to 1000 C., its destructive reaction with ammonia (Equation 4) is catalyzed by increasing temperature and becomes appreciable at about 50 C. depending on other environmental conditions.

The time required to complete the chloramine tertiary amine reaction is dependent upon external conditions, thoroughness of contact, and intrinsic process variations apparent to one skilled in the art. When a stoichiometric quantity of chloramine is used, the end point of the reaction can be determined by the complete loss of oxidizing power (eg to potassium iodide-acetic acid) of the same reaction medium. This test is clearly described by Omietanski (US. Patent 2,955,108). It is convenient, especially When excess chloramine is used, to let the reaction mixture set from 1 to 24 hours until all of the chloramine is consumed.

Once all of the amine has been converted, the resulting solution containing suspended ammonium chloride is heated to about C. and filtered. The filtrate is evaporated to dryness under vacuum, yielding N-alkyl- 2,2-dihydroxydiethy1 hydrazinium chloride. Yields are generally in the neighborhood of to and the purity is usually 93-97%.

A solution of thionyl chloride, SOCl is prepared by dissolving a convenient amount of the liquid in a suitable solvent, such as benzene or chloroform. The quantity of thionyl chloride used should bear a stoichiometric relationship to the quantity of hydrazinium to be added. The concentration of the solution is not critical,

but again it should be kept in mind that too much excess solvent is undesirable. The hydrazinium salt is gradually added as a solid in small quantities, the reaction temperature being kept at about 40 C. After the end of the introduction, the mixture is placed under vacuum and evaporated to dryness. The product is generally recrystallized.

To assist in identification and characterization, it is frequently necessary to convert hydrazinium chlorides to pure crystalline derivatives which retain the hydrazinium cation. The melting points, crystal habits, X-ray diffraction patterns, and elemental analyses of these derivatives can then serve as proof of the identity of the original hydrazinium chloride. It has been found that potassium hexafiuorophosphate is an inexpensive derivatizing reagent which yields, quickly and quantitatively, pure, uniquely characteristic products merely on addition to a solution of the quaternized hydrazinium salt (Equa tion These novel salts are crystalline, non-hygroscopic, and readily recrystallizable. They have characteristic and reproducible crystal habits and melting points.

The advantage of my invention can be clearly seen by considering the three following examples. The first two show processes disclosed in prior art. It is to be noted that only low yields are obtained. The third example shows my method, by which good yields are obtained. In all three examples, the desired product is N-methyl2,2'-dichlorodiethyl hydrazinium chloride.

Example I Gaseous ammonia was added to a slurry of 19.2 g. (0.1 mole) of methyl-bis-chloroethyl amine hydrochloride in 750 ml. ether to free the amine from its salt. Addition of 750 ml. (0.3 mole) of an ether/chloramine solution gave a reaction mixture 0.067 N in amine and 0.2 N in chloramine. The mixture bubbled and deposited a dark, gummy solid. The yield of product recoverable from the substance was in the order of 3%.

Example 11 A mixture containing 24 g. (0.125 mole) of methylbis-chloroethyl amine hydrochloride in 1500 ml. of isopropyl alcohol was ammoniated for 15 minutes to free the amine, and then chloraminated with 0.3 mole of filtered chloramine by the general method of Sisler et al. (US. Patent 2,710,248). Filtration of the ammonium chloride and evaporation of the filtrate gave a gummy solid. Yield of desired product was approximately 2%.

Example 111 119 grams (1 mole) of methyl diethanol amine were dissolved in 1 liter of warm 2-propanol. A stream of chloramine and ammonia was then introduced into the solution, kept at room temperature during the course of the run. A total of 4 moles of chloramine were added within 7 hours. The resulting solution, containing suspended ammonium chloride, was then heated to 75 C. and filtered. The filtrate was evaporated to dryness under vacuum, yielding 154 grams of white crystalline product. An analysis of this material as N-methyl-2,2'- dihydroxydiethyl hydrazinium chloride gave a purity of 95% This corresponds to a yield of 85.5%.

34.1 grams (0.2 mole) of hydrazinium salt prepared as described above were added in portions to a stirred solution of 65 grams of thionyl chloride kept at 40 C. A gas escaped, following each addition. After the end of the introduction, the mix was placed under vacuum, and evaporated to a light brown colored material. Re-

4. crystallization of this product gave 5 grams of the desired N methyl 2,2 dichlorodiethyl hydrazinium chloride. This is a 12% yield.

The compounds of my invention have proven to be effective in the treatment of cancer of rats. Carefully controlled studies were carried out in accordance with the Specification for Screening Chemical Agents and Natural Materials Against Animal Tumors as set out by the cancer Chemotherapy Division of the National Cancer Institute, National Institutes of Health. Hydrazinium salts as described above were screened against Sarcoma 180, mamary adenocarcinoma, or Ehrlich ascites, and lymphoid leukemia. The tests carried out showed that the hydrazinium derivatives of nitrogen mustards are generally as effective as the nitrogen mustards themselves, but with a considerably decreased mortality rate among test animals, thereby demonstrating'the reduction in toxicity.

It is obvious to one skilled in the art that my process for the production of nitrogen mustard derivatives via the thionyl chloride route is applicable to any compounds of the following groups:

(1) N-alkyl-dichlorodialkyl hydrazinium chloride. (2) Tris(chloroalkyl) hydrazinium chloride.

I claim:

1. A process for the preparation of compounds from the group consisting of N-alkyl-2,2'-dichlorodiethyl hydrazinium chloride and tris(2-chloroethyl) hydrazinium chloride which comprises dissolving a member from the group consisting of N-alkyl-2,2-dihydroxydiethyl amine and tris(2-hydroxyethyl) amine is 2-propanol, treating the solution with an approximately stoichiometric quantity of gaseous chloramine diluted with ammonia at a temperature below 50 C., thereby forming a member of the group consisting of N-alkyl-Z,2'-dihydroxydiethyl hydrazinium chloride and tris(hydroxyethyl) hydrazinium chloride, evaporating the solution to dryness, recovering the product hydrazinium chloride, dissolving thionyl chloride in a solvent selected from the group consisting of chloroform and benzene, treating the hydrazinium chloride with an approximately stoichiometric amount of the thionyl chloride solution at about 40 C., evaporating the mixture to dryness and finally recovering the product.

2. A process for the preparation of N-alkyl-2,2'-dichlorodiethyl hydrazinium chloride in which the alkyl radical has from 1 to 4 carbon atoms comprising dissolving an alkyl diethanol amine in which the alkyl radical has from 1 to 4 carbon atoms in 2-propanol, introducing at least a stoichiometric quantity of chloramine diluted with ammonia into said solution while maintaining the reaction mixture at temperatures below 50 C., heating said solution to about C., filtering and evaporating said solution to dryness, adding the hydrazinium salt formed thereby to an approximately stoichiometric quantity of thionyl chloride dissolved in a solvent selected from the group consisting of chloroform and benzene at about 40 C., and evaporating the mixture formed thereby to dryness.

3. The process described in claim 2 wherein said N- alkyl-2,2-dichlorodiethyl hydrazinium chloride is N- rnethyl-2,2-dichlorodiethyl hydrazinium chloride, and said alkyl diethanol amine is methyl diethanol amine.

4. A process for the preparation of N-alkyl-2,2'-dichlorodiethyl hydrazinium chlorides in which the alkyl radical has from 1 to 4 carbon atoms comprising dissolving N-alkyl-2,2-dihydroxydiethyl amine in 2-propanol warmed to between 35 and 60 C., cooling said solution to room temperature, treating said solution with a stoichiometric quantity of gaseous chloramine diluted with ammonia at room temperature for sufficient time for the chloramination reaction to go to completion heating the resultant-reaction mixture to about 75 C., filtering said reaction mixture, evaporating the filtrate to dryness, gradually adding the residue formed thereby to a 5 stoichiometric quantity of thionyl chloride dissolved in a solvent selected from the group consisting of chloroform and benzene at about 40 C., and evaporating the mixture formed thereby to dryness and recovering the product.

5. The process described in claim 4 wherein said N-alkyl-2,2-dichlorodiethyl hydrazinium chloride is N- methyl-2,2'-dichlorodiethyl hydrazinium chloride and said N-alky1-2,2'-dihydroxydiethyl hydrazinium chloride is N-methyl-2,2-dihydroxydiethy1 hydrazinium chloride.

References Cited by the Examiner UNITED STATES PATENTS OTHER REFERENCES Oka: Chemical Abstracts, vol. 52, p. l5568i (1958).

0 CHARLES B. PARKER, Primary Examiner.

Claims (1)

1. A PROCESS FOR THE PREPARATION OF COMPOUNDS FROM THE GROUP CONSISTING OF N-ALKYL-2,2--DICHLORODIETHYL HYDRAZINIUM CHLORIDE AND TRIS(2-CHLOROETHYL) HYDRAZINIUM CHLORIDE WHICH COMPRISES DISSOLVING A MEMBER FROM THE GROUP CONSISTING OF N-ALKYL-2,2''-DIHYDROXYDIETHYL AMINE AND TRIS(2-HYDROXYETHYL) AMINE IS 2-PROPANOL, TREATING THE SOLUTION WITH AN APPROXIMATELY STOICHIOMETRIC QUANTITY OF GASEOUS CHLORAMINE DILUTED WITH AMMONIA AT A TEMPERATURE BELOW 50*C., THEREBY FORMING A MEMBER OF THE GROUP CONSISTING OF N-ALKYL-2,2''-DIHYDROXYDIETHYL HYDRAZINIUM CHLORIDE AND TRIS(HYDROXYETHYL) HYDRAZINIUM CHLORIDE, EVAPORATING THE SOLUTION TO DRYNESS, RECOVERING THE PRODUCT HYDRAZINIUM CHLORIDE, DISSOLVING THIONYL CHLORIDE IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF CHLOROFORM AND BENZENE, TREATING THE HYDRAZINIUM CHLORIDE WITH AN APPROXIMATELY STOICHIOMETRIC AMOUNT OF THE THIONYL CHLORIDE SOLUTION AT ABOUT 40*C., EVAPORATING THE MIXTURE TO DRYNESS AND FINALLY RECOVERING THE PRODUCT.