Novel process for the preparation of bronopol

A process of forming 2-bromo-2-nitro-1,3-propanediol by contacting a 5-nitro-1,3-dioxane with bromine under alkaline conditions and hydrolyzing the brominated product.

BACKGROUND OF THE INVENTION 
The present invention relates to a novel process to form 
2-bromo-2-nitro-1,3-propanediol (commonly known as "bronopol"). The 
present process provides a means of forming bronopol using readily 
obtained materials under mild and easily handled conditions suitable for 
industrial application. 
Bronopol is a highly desired material utilized as a biocide and as a 
medicament in toiletries such as shampoos and the like. 
Bronopol has been previously prepared from 2-oximino-1,3-propanediol, 
2-nitro-1,3-propanediol, and oximinomalonic acid diethyl ester. In most 
cases the required processes provided low yields and, in certain 
instances, utilizes poorly accessible starting materials. In addition, the 
processes normally entail the generation of decomposable and dangerous 
intermediates which require special equipment and handling practices. The 
expense of the reactants and equipment required, as well as the special 
handling needed leads to unsatisfactory processes for industrial 
application. 
The major commercial method of producing bronopol is disclosed in U.S. Pat. 
Nos. 3,658,921 and 3,711,561. The process entails the initial formation of 
sodium 2-nitro-1,3-propanediol by reacting formaldehyde with nitroemethane 
and with an alkali metal hydroxide such as sodium hydroxide. The formed 
idol must then be added slowly to an appropriate amount of bromine to 
produce the desired bronopol. The difficulty with this method relates to 
the sodium nitro-1,3-propanediol which is known to be an unstable material 
which decomposes with catastrophic results. 
It is highly desired to have a process capable of forming bronopol which 
utilizes readily available and easily handled materials. 
SUMMARY OF THE INVENTION 
The present invention is directed to a process which is readily adaptable 
to industrial application and utilizes reactants and conditions which do 
not present a handling problem. 
The instant process comprises bromination of certain 5-nitro-1,3-dioxanes 
under certain conditions described below to form the corresponding 
5-bromo-5-nitro derivative and hydrolyzing the brominated derivative to 
give the desired bronopol. 
DETAILED DESCRIPTION OF THE INVENTION 
The present process provides the desired bronopol using readily available 
reactants under conditions easily adoptable for industrial application. 
The total synthesis can be accomplished by the following reactions: 
1. Nitromethane is reacted with three moles of formaldehyde to form 
tris(hydroxymethyl)nitromethane (I). 
##STR1## 
This Henry Reaction is carried out by contacting the nitromethane and 
formaldehyde in a solvent normally selected from a lower alkyl alcohol or 
water (preferably methanol) in the presence of a catalytic amount of base 
such as sodium or potassium hydroxide. The formaldehyde should be present 
in at least stiochiometric amounts based on nitromethane (i.e. 3 moles of 
formaldehyde per mole of nitromethane). This reaction is known and the 
product can be commercially obtained. This product, unlike the 
dihydroxymethyl nitromethane sodium salt used in U.S. Pat Nos. '921 and 
U.S. Pat. No. '561, is a stable product which is readily obtained in very 
high yields because the substitution is allowed to go to completion. 
2. The formed tris(hydroxymethyl)nitromethane (I) is then reacted with a 
ketone in the presence of a catalytic amount of a strong acid to form the 
corresponding acetal, the 5-hydroxymethyl-5-nitro-1,3-dioxane which has 
substitution in the 2 position (II), in good yields. 
##STR2## 
Each R and R' can independently be selected from hydrogen or an alkyl, 
cycloalkyl or aryl group or R and R' can together form an alkylene group, 
and preferably a C.sub.4 -C.sub.6 alkylene group. The particular identity 
of R and R' is not critical to this reaction nor to the overall synthesis. 
However, the dialkyl ketones are preferred due to their availability. 
Examples of suitable ketones include acetone, methyl ethyl ketone, diethyl 
ketone, cyclohexanone and the like. The reaction can be run neat using 
excess ketone as the reaction medium (preferred) or by using an inert 
solvent in which both compound I and the ketone are soluble. The reaction 
is catalyzed by the presence of catalytic amounts (normally from about 
0.001 to 1 weight percent based on the weight of ketone) of a strong acid, 
such as a mineral acid (HCl H.sub.2 SO.sub.4, and the like) or a strong 
organic acid such as glacial acetic acid, toluene sulfonic acid and the 
like. 
The above reaction (2) produces water as a by-product. The water must be 
removed in order to prevent reversion of the formed acetal back to the 
ketone and alcohol. When the reaction utilizes a high boiling ketone 
(having a B.P. higher than water and suitable for separating the water 
from ketone by distillation), such as cyclohexanone, the water by-product 
can be removed by azeotropic distillation during the progress of the 
reaction. When a low boiling ketone, having a boiling point lower than 
water, such as acetone, is used the procedure requires the presence of a 
dessicant, such as boron trifluoride etherate or a molecular sieve which 
collects water or the like to remove the water as it forms. 
Although the above reaction utilizes readily attainable and inexpensive 
reactants, the need to remove the water by-product as it forms may add to 
the cost of the reaction and the overall synthesis. If such economics 
presents a factor, the formation of an acetal can be accomplished without 
the production of water by alternate reactions, as described hereinbelow. 
2(A). The tris(hydroxymethyl)nitromethane (I) can be converted to an acetal 
by reacting it with a vinyl ether in the presence of a catalytic amount of 
a strong acid (such as mineral acids, glacial acetic acid and the like) by 
the following reaction: 
##STR3## 
R can represent any alkyl, cycloalkyl or aryl group and is preferably a 
lower alkyl. Examples of suitable vinyl ethers include ethyl vinylether, 
methyl vinylether and the like. The resultant by-product alcohol does not 
interfere with the reaction. 
2(B). Again, as an alternate means, the desired acetal compound can be 
provided by reacting the tris(hydroxymethyl)nitromethane (I) with certain 
gem diethers in the presence of a catalytic amount of a strong acid (such 
as mineral acid, glacial acetic acid and the like) by the following 
reaction: 
##STR4## 
The symbols, R and R' are the same hydrocarbon as described above with 
respect to reaction 2 and R" can be any alkyl, preferably a lower alkyl 
such a methyl, ethyl, propyl and the like. Examples of such gem ethers 
include 2,2-dimethoxypropane 2,2-diethoxypropane, 3,3-dimethoxypentane, 
3,3-diethoxy pentane and the like. 
The reaction 2A and 2B can be carried out by taking up compound I in excess 
of the ether and warming the system to a temperature of from about 
20.degree. C. to 80.degree. C. with temperatures of from 20.degree. C. to 
50.degree. C. being preferred. 
The resultant acetals, (II), (IIa) and (IIb), are all readily formed in 
good yields which is normally greater than about 90 percent. The acetal 
can be separated from the reaction mixture by conventional means such as 
by distillation where the product is a liquid or by filtration where the 
product is a solid. The exact nature of the product depends on the 
identity of R and R'. 
3. The 5-hydroxymethyl-5-nitro-1,3-dioxane derivatives (II), (IIa) or (IIb) 
are readily converted into the corresponding 5-nitro-1,3-dioxane compound 
by treating the derivative with alkali, such as an alkali (preferably) or 
alkaline earth metalhydroxide (MOH), and then acidification of the 
solution according to a procedure suggested in Roczniki Chemii Ann. Soc. 
Chim. Polonorum 47 409 (1973) as represented by the conversion of (II) as 
follows: 
##STR5## 
The reaction can be carried out by taking the acetal up in an aqueous 
solution of an alkali metal hydroxide such as sodium or potassium 
hydroxide. The hydroxide concentration may be from about 5 to 25 percent 
or greater with from 10 to 20% being preferred. The presence of excessive 
amounts of water (above that required to retain a solution) should be 
avoided. The solution should be agitated as by stirring for a period of 
time of from 10 minutes to 200 minutes, with from about 30 to 100 minutes 
normally being satisfactory, while maintaining an elevated temperature of 
from about 30.degree. to 100.degree. C. (40.degree.-80.degree. C. being 
preferred). The solution is then cooled to a reduced temperature to less 
than about 20.degree. C. and preferably from about 0.degree. C. to 
20.degree. C. prior to slow introduction of the acid. Although 
concentrated mineral acid can used, it is preferred to use a strong 
organic acid to minimize the water concentration and thereby enhance the 
precipitation of product III which can be readily separated by 
conventional means such as filtration. When product IIa is used the 
resultant product will be the corresponding 
2-substituted-5-nitro-1,3-dioxane(IIIa). 
The 5-nitro-1,3-dioxane derivative III or IIIa, whether formed by the above 
synthesis route or by other methods (such as one proposed by Linden et 
al., J. Org. Chem. 21 1175 (1956) by direct cyclization of 
2-nitropropanediol-1,3) has been found to be readily convertible into 
bronopol. The process requires the bromination of a product III or IIIa 
followed by hydrolysis of the resultant brominated material. 
4. The product III or IIIa is taken up in a liquid which is inert to akali 
and/or bromine and which is a solvent for the nitronate salt initially 
formed. Such liquids include water, tertiary alcohols, such as 
t-butylalcohol and the like; sulfoxides, such as dimethylsulfoxide and the 
like; and amides such as dimethylfomamide, dimethylacetamide and the like. 
The most preferred material is water. 
Compound III or IIIa is introduced into an aqueous solution containing at 
least a stoichiometric equivalent of an alkali metal hydroxide (MOH) such 
as sodium hydroxide, potassium hydroxide and the like. Normally, excess 
amounts (preferably, up to about 1.1 mole per mole of compound III or 
IIIA) of the hydroxide is used. The concentration of hydroxide in the 
aqueous solution is normally from about 5 to 30 percent. Contacting of the 
alkali metal hydroxide and compound (III) or (IIIa) can be accomplished 
under temperatures from about 10.degree. C. to about 100.degree. C. with 
from about 20.degree. to 60.degree. C. being preferred. The reaction can 
be conducted at ambient conditions. The sodium nitronate salt is soluble 
in aqueous solution and provides a stable intermediate material which can 
be directly brominated. The bomination is accomplished by introducing 
liquid bromine into the aqueous solution in at least stoichiometric 
amounts based on the amount of compound (III) or (IIIa) being treated. 
Small excesses of bromine will be consumed by any excess of the alkali 
metal hydroxide present in the solution. The bromination is exothermic and 
should be maintained at temperatures of from 5.degree. C. to 50.degree. C. 
with from 10.degree. C. to 30.degree. C. being preferred. Control can be 
readily accomplished by any conventional means such as by incremental 
introduction of bromine, the use of a cooling means in or surrounding the 
reaction vessel or the like. 
Alternately, the bromination can be conducted by the cointroduction of an 
alkali metal hydroxide (MOH) and bromine liquid into a suspension of 
compound (III) or (IIIa) (i.e. an aqueous suspension). The resultant 
5-bromo-5-nitro-1,3-dioxane derivatives (IV) are insoluble in the required 
solvent and, therefore, are readily separated and recovered, if desired, 
by filtration. The overall reaction is represented as follows: 
##STR6## 
Alternately to reactions 3 and 4 as described hereinabove, the acetal 
compund (II), (IIa) or (IIb) can be directly converted into the 
corresponding 5-bromo-5-nitro-1,3-dioxane derivative IV by taking up the 
acetal II, IIa or IIb in a liquid which is inert to base and bromine as 
described above. Water is the preferred liquid. The acetal is reacted with 
a molar excess of an alkali metal hydroxide. as described with respect to 
reaction 3 above. The resultant solution is cooled to a temperature of 
from about 10.degree. C. to 50.degree. C. (preferably from about 
10.degree. C. to 30.degree. C.) and liquid bromine is added to the 
solution while maintaining the lowered temperature as described with 
respect to reaction 4 above. The resultant 5-bromo-5-nitro-1,3-dioxane 
derivative (IV) is separated from the reaction media by conventional 
methods such as by filtration, or evaporation of the liquid media or the 
like. 
5. Bronopol is recovered in good yields by contacting product IV with a 
strong acid. 
##STR7## 
The formation of bronopol from product IV proceeds readily by taking 
product IV up in water (preferred) or a lower alkyl alcohol such as 
methanol, ethanol, propanol or the like to provide a solution and 
introducing a mineral acid such as hydrochloric, sulfuric acid into the 
solution. Although the exact mode of contacting the acid and product IV is 
not critical, it is preferred that the acid be introduced slowly and the 
solution be maintained at moderate temperatures such as ambient to 
75.degree. C., preferably from 30 to 50.degree. C. Small amounts of acid 
is sufficient and may normally be from 0.01 to 0.1 mole per mole of 
product IV. Larger amounts of acid may be used but is normally 
unnecessary. Bronopol can be recovered from the solution by any 
conventional manner such as by evaporation of the liquid solvent, or by 
use of a non-solvent to precipitate the product V, or other conventional 
means. Bronopol is known to be soluble in water, lower alcohols and 
ethylacetate and substantially insoluble in liquids such as chloroform, 
acetone, diethylether, benzene, ligroin and the like. 
The subject process provides a new route for the production of bronopol 
using readily available and easily attainable reactants. The process 
requires conventional handling conditions which do not present any 
problems which may result in catastrophic results, such as encountered by 
the present commercial mode of forming bronopol. 
The present process provides a means of converting 5-nitro-1,3-dioxane 
derivatives into bronopol by deprotonation and bromination under certain 
conditions which retain the dioxane ring and then hydrolyzing the 
resultant brominated derivative. Further, the present invention provides a 
process for synthesizing bronopol starting with nitromethane and without 
encountering the hazardous material, sodium 
bis(hydroxymethyl)nitromethane, of the present commercial process. 
The following examples are given for illustrative purposes only and are not 
meant to be a limitation on the invention as defined by the claims 
appended hereto. All parts and percentages are by weight unless otherwise 
indicated.

EXAMPLE 1 
A 100 ml round bottom flask equipped with a stir bar and reflux condenser 
topped with a nitrogen inlet was charged with 15.1 g (0.1 mol) of 
tris(hydroxymethyl) nitromethane and 22 ml (0.3 mol) of acetone. The 
mixture was heated until all the tris(hydroxymethyl)nitromethane had 
dissolved and then was cooled to 15.degree.-20.degree. C. The trimethylol 
compound crystallized in fine needles. Boron trifluorideetherate (13 ml, 
0.1 mol) was added with stirring. The temperature rose to 55.degree. C. 
and crystals of product began to separate. After five minutes, the mixture 
was poured into a stirred mixture of 110 ml of saturated sodium 
bicarbonate solution and excess ice. After stirring for 15 minutes, the 
product, 2,2-dimethyl-5-hydroxymethyl-5-nitro-1,3-dioxane was collected by 
filtration, washed with cold water and dried in vacuo. The yield was 
determined to 88%. 
EXAMPLE 2 
To a 100 ml round bottom flask equipped with a stir bar, soxhlet extractor 
and reflux condensor topped with a nitrogen inlet was added 2 g (0.013 
mol) tris)hydroxymethyl)nitromethane, 1.42 g (0.014 mol) cyclohexanone, 
0.2 g p-toluenesulfonic acid and 60 ml acetonitrile. The soxhlet thimble 
was filled with 3A molecular sieves. The reaction mixture was then 
refluxed for 24 hours with the sieves being changed at 6 hours. After 
cooling to room temperature, all volatiles were removed in vacuo. The 
solid remaining was then dissolved in 30 ml CH.sub.2 Cl.sub.2 and dried 
over MgSO.sub.4. After one hour, the MgSO.sub.4 was filtered off and the 
CH.sub.2 Cl.sub.2 removed to give 
2,2-pentamethylene-5-hydroxymethyl-5-nitro-1,2-dioxane in 73% yield. 
EXAMPLE 3 
Into a 250 ml round bottom flask equipped with a stir bar, thermometer and 
reflux condensor topped with a nitrogen inlet was added 5.73 g (0.03 mole) 
of 2,2-dimethyl-5-hydroxymethyl-5-nitro-1,3-dioxane and 70 ml 10% sodium 
hydroxide which was heated to 60.degree. C. for one hour. The solution was 
cooled to 5.degree. C. and at this temperature acidified to pH 5 with 
concentrated acetic acid. The precipitated solid was filtered off and 
dried to give 5.2 g (92%) of 2,2-dimethyl-5-nitro-1,3-dioxane m.p. 
60.degree.-61.degree. C. .sup.1 H NMR in CD.sub.3 OD also confirmed the 
structure. 
EXAMPLE 4 
The reaction was run as described in Example 3 except that 
2,2-pentamethylene-5-hydroxymethyl-5-nitro-1,3-dioxane was used instead of 
2,2-dimethyl-5-hyroxymethyl-5 -nitro-1,3-dioxane. The yield of product 
2,2-pentamethylene-5-nitro-1,3-dioxane was 81%. 
EXAMPLE 5 
Into a 25 ml round bottom flask was placed 5 ml of water amd 900 mg of (5.6 
mmoles) of 2,2-dimethyl-5-nitro-1,3-dioxane as formed in Example 3 above. 
The resulting suspension was stirred and cooled to 10.degree. C. Seven ml 
of 1 N sodium hydroxide solution was added incrimentally over a short time 
period. All of the compound went into solution. The solution was then 
treated with 895 mg of liquid bromine. A solid separated from the solution 
with disappearance of the bromine color. The resultant suspension was 
stirred for about 10 minutes after all of the bromine was added and then 
extracted with two portions of 5 ml of dicloromethane and then tried over 
MgSO.sub.4 with 50 mg of charcoal (Norite A), filtered and dired in vacuum 
at 25.degree. C. to give 1.28 gm (95.2%) of pure white crystals having a 
MP of 83.degree.-85.degree. C. and a 'H NMR consistant with 
2,2-dimethyl-5-bromo-5-nitro-1,3-dioxane. 
EXAMPLE 6 
The reaction is run as described in Example 5 except that 
2,2-pentamethylene-5-nitro-1,3-dioxane is used instead of 
2,2-dimethyl-5-nitro-1,2-dioxane. The yield of product is similar to that 
obtained in Example 5. 
EXAMPLE 7 
To a 50 ml round bottom flask equipped with a stir bar and reflux condensor 
topped with a nitrogen inlet was added 0.5 g (.004 mol) 
2,2-dimethyl-5-nitro-5-bromo-1,3-dioxane, 10 ml methanol and 0.3ml 
concentrated HCl. The reaction was heated to 35.degree.-40.degree. C. for 
1 hour. After cooling to room temperature, the volatiles were removed to 
give crystalline bronopol (95% yield) which on recrystallization from 
acetone had a melting point of 120.degree. C. 
EXAMPLE 8 
Into a 25 ml round bottom flask is placed 5 ml of water and 1070 mg (5.6 
mmoles) of 2,2-dimethyl 5-hydroxymethyl-5-nitro-1,3-dioxane as formed in 
Example 2 above. The resulting suspension is treated with 13 ml of 10% 
sodium hydroxide solution and heated to 60.degree. C. for one hour to form 
a solution. The solution is cooled to 10.degree. C. and treated with 895 
mg of liquid bromine. A solid separates from solution with disappearance 
of bromine color. The resultant suspension is extracted with several 
portions of dicloromethane and then dried with over MgSO.sub.4, filtered 
and dried under vacuum at 25.degree. C. to produce the 5-bromo-5-nitro 
derivative as in Example 5 above.