NO137896B - ANALOGICAL PROCEDURES FOR THE PRODUCTION OF THERAPEUTIC ACTIVITIES, OPTICALLY ACTIVE 1,4-BENZODIAZEPINES - Google Patents

Description

Process for the production of new nitro-acetals.

The present invention relates to a

process for the preparation of new nitroacetals with the following general formula:

in which R and R, represent hydrogen or an alkyl radical, R, and R3 represent hydrogen or halogen or an alkyl, nitroalkyl, nitro, aryl, alkaryl, arylalkyl, cycloalkyl, haloalkyl or nitrazaalkyl radical, in that R2 and R3 can be the same or different, while A denotes an alkylene radical.

The nitro-acetals which are produced by the process according to the invention, and in particular the gem-dinitroacetals, are very good plasticizers for use in the production of polyurethane binders for solid high-energy propellants for rockets. These acetals are also suitable as plasticizers for nitrocellulose and nitropolymers. These plasticizers contribute to increasing the energy of the propellants in which they are mixed due to their high content of nitro groups and are therefore better than the currently available commercial plasticizers, as such commercial products do not contain nitro groups and are therefore practically without ability to develop energy. Moreover, nitroacetals produced by the method according to the invention are compatible with polyurethane systems in which the monomers contain gem-dini-tro or nitraza groups. Almost all commercially available plasticizers are incompatible with such systems.

When using these nitroacetals as plasticizers during polymerization into nitropolymers, such polymers can be produced in the presence of the plasticizer or the plasticizer can be mixed into the nitropolymer after it has been produced. The plasticizers are mixed into the nitropolymers in quantities that are preferably within the range from approx. 10 percent to approx. 40 wt. calculated on the weight of the mixture. When acetals are used as plasticizers for polyurethanes that do not contain nitro groups, the technique of mixing the plasticizer into the binder used with nitropolymers is also used. The plasticizers are preferably mixed into the propellants in proportions up to approx. 15 wt. of their weight.

The nitro-substituted polyurethane and

-polyurethane propellants can be used as a primary propellant source in rocket-powered vessels and can also be used as propellants for artillery projectiles. When they are used as a primary propellant source for rocket-powered vessels, they can conveniently be ignited by conventional means of ignition. The propellant is preferably cast in tube form and dampened on con-

conventional way with relatively inert resins such as non-nitrated polyurethane foam or polyester resins, and placed in a chamber whose one end is open and leads to a conventional venturi nozzle for rockets. During ignition, large quantities of gases are developed which are blown out through the nozzle and thereby develop driving force.

The new method according to the present invention comprises reacting an aldehyde or ketone with a nitroalcohol in accordance with the following reaction scheme:

In this reaction scheme, R, R1, R2, R3 and A have the meanings given above.

It will be understood that a large number of different compounds can be prepared by reacting a suitable aldehyde or ketone with a suitable nitroalcohol in accordance with the method described herein. Examples of aldehydes and ketones which are suitable as reaction components in the method according to the invention are: disobutyraldehyde, isopentanaldehyde, 2-methyl-butyraldehyde, 2-methyl-pentanaldehyde, 3-methyl-pentanaldehyde,

2-methyl-caproaldehyde, 2-ethylcaproaldehyde, enanthadehyde, 2-ethyl-enanthaldehyde, 2-isopropyl-enanthaldehyde, methyl-isopropyl ketone, methyl-isobutyl ketone,

ethyl isobutyl ketone, ethylhexyl ketone,

ethyl isohexyl ketone, diisopropyl ketone, dibutyl ketone, diethyl ketone and methyl octyl ketone. Examples of nitroalcohols which are suitable as reaction components in this method are: 4-nitraza-2-nitro-n-pentanol; 4-nitraza-2-chloro-n-pentanol; 4-nitraza-2-phenylmethyl-n-pentanol; 4-chloro-2-methyl-2-nitro-n-butanol; 4-chloro-2,2-di-nitro-n-butanol; 4-chloro-2-cyclohexyl-2-nitro-n-butanol; 2-nitro-2-tolyl-n-hexan-ol; 2,5-dinitro-2-p-tolyl-n-pentanol; 2-chloro-2-nitro-3-phenyl-propanol; 3,3-dinitro-3-phenylpropanol and 3,3-dinitro-1-butanol.

According to the invention, the aldehyde or ketone starting materials for the reaction described above can be formed in situ. Thus, a polymer can be added to the reaction mixture which is depolymerised to form a suitable aldehyde or ketone, together with a suitable depolymerisation catalyst. For example paraformaldehyde, which is a polymer of formaldehyde, can be added together with one of the polymerization catalysts which cause this polymer to break down in situ to form formaldehyde. Likewise, paraldehyde, which is a trimer of acetaldehyde, can be depolymerized in situ to form acetaldehyde as starting material for the reaction.

For said depolymerization, any suitable known depolymerization catalyst can be used for the in situ formation of aldehydes or ketones. Catalysts which are particularly well suited for this purpose are the conventional acidic esterification catalysts such as sulfuric acid, ferric chloride, p-toluenesulfonic acid, m-benzene disulfonic acid, zinc chloride, HC1, HF, BF3, boron trifluoride complex compounds, etc.

The reaction according to the invention is preferably carried out in a medium consisting of an inert solvent. Any organic solvent can be used as such a medium, such as e.g. benzene, toluene, chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride. It is preferred to use an organic solvent as reaction medium, but the reaction according to the invention can be carried out in any other suitable liquid which is compatible with the reaction components. an excess of one of the reaction components such as 2,2-dinitropropanol or a liquid catalyst such as sulfuric acid possibly containing small amounts of water is used. For practical reasons, it is preferred to carry out the reaction according to the invention in the presence of a catalyst. The catalysts mentioned above as suitable for in situ formation of aldehydes and ketones are also suitable for the reaction according to the invention. When depolymerization in situ is used, the same substances can therefore be used to carry out this depolymerization and to catalyze the reaction. Moreover, compounds which are capable of forming alcoholates such as e.g. calcium chloride, suitable catalysts for the reaction according to the invention.

The reaction temperature is not critical to the performance of this reaction, the only notable effect of an increase or decrease in temperature being a corresponding increase or decrease in the reaction rate. However, for economic reasons and for expediency reasons, it is preferred to use temperatures in the range from 20 to 50° C when carrying out the method according to the invention.

In the following, some embodiments of the invention are described as examples.

Example 1.

Preparation of formaldehyde-bis-(2,2-dinitropropyl)-acetal.

In a 100 ml flask equipped with a stirrer and thermometer were placed 15 ml of ethylenedichloride, 80.0 g of 2,2-dinitropropanol (0.50 M, 93.6% pure) and 19 ml of concentrated (96% 's) sulfuric acid. During the mixing, a small amount of heat was generated and moderate cooling was used. At a temperature of 20-25° C, 7.8 g (0.24 M) paraformaldehyde (91 percent in the form of flakes) was added, whereby a weak exothermic reaction took place. The temperature was kept below 30° C by means of cooling. The stirring was continued for 1 hour at 25-30° C. The upper layer of the reaction mixture was then separated by means of methylene chloride and the reaction mixture extracted with this solvent. The organic phase was washed twice with dilute sodium hydroxide solution, twice with water and then dried over sodium sulphate. The solvent was then removed in vacuo, whereby 66.7 g (corresponding to 90 per cent of the theoretical yield) of 25

a viscous, colorless liquid, n D 1.4637.

40 g of this impure acetal was dissolved in 100 ml of denatured ethanol. At 12° C, seeding crystals were added. The mixture was cooled to -20° C and the colorless product thus obtained was filtered off, washed and dried. The yield was 30.2 g, corresponding to 76 per cent of the theoretical amount.

Elemental analysis of a sample that had been recrystallized twice from methanol and had a melting point of 32.5-33.5° C gave the following result: Calculated for C7<H>12N4O10: C 26.93 percent, H

3.87 per cent, N 17.95 per cent.

Found: C 27.41 per cent, H 3.74 per cent, N 17.95 per cent.

27.28 percent 3.75 percent 18.22 percent

Example 2.

Preparation of acetaldehyde-bis-(2,2-dinitropropyl)-acetal.

1/10 mol 2,2-dinitropropanol (15.8 g), 4.0 g calcium chloride (0.036 M, A.R., 20 mesh) and 2.2 g acetaldehyde (0.050 M) were mixed in a 50 ml round bottom flask. The flask was fitted with a stopper which was attached to keep it in place and avoid evaporation of the acetaldehyde. Most of the calcium chloride gradually dissolved. After isolation of the impure acetal by proceeding as indicated in example 1, 7.6 g were obtained (corresponding to 46 per cent of the theoretical

25 changes) of a colorless oil, n D 1.4588.

This acetal was purified by recrystallization from diisopropyl ether. 4.2 g of product was obtained, corresponding to a yield of 26 per cent,

n ^ 1.4604.

Example 3.

Production of acetaldehyde bis-(2, 2-dinitropropyl) acetal.

In this example, the production of acetaldehyde-bis-(2,2-dinitropropyl)-acetal is described with the formation of acetaldehyde starting material in situ from paraldehyde and the use of an excess of sulfuric acid as reaction medium.

In a 50 ml, 3-necked flask equipped with a stirrer, thermometer and dropping funnel were placed 31.5 g (0.20 M, 95.2 percent pure) 2,2-dinitropropanol and 15 ml concentrated (96 percent ) sulfuric acid. The clear, colorless solution thus obtained was added 4.4 ml (0.10 M as acetaldehyde) paraldehyde dropwise and with good stirring. The temperature was maintained between 0 and -5°C during the 10 minute addition period. The mixture was then stirred at a temperature below 0° C. for 1 hour, during which the color gradually changed to orange-brown. The apparently homogeneous reaction mixture was extracted twice with a total of 120 ml of methylene chloride. From the extracts, 3.7 g (corresponding to 11 percent of the theoretical 4.U .4. ^ - _ 25 1.4638. yield) of a light brown oil was obtained, n D

Example 4.

Production of acetaldehyde bis-(2, 2-dinitropropyl) acetal.

This example describes the production of acetaldehyde-bis-(2,2-dinitropropyl)-acetal by reaction of acetaldehydes which are formed in situ from paraldehyde, with 2,2-dinitropropanol in methylene chloride as reaction medium.

15.8 g (0.10 M, 95% pure) of 2,2-dinitropropanol, 25 ml of methylene chloride, 3 drops of concentrated sulfuric acid and 2.2 ml (0.050 M) of paraldehyde were placed in a 100 ml flask. After 21 hours of boiling under reflux cooling, approx. 0.5 ml of water (55% of the theoretical amount) was removed azeotropically. The solution had turned a very dark brown colour. The impure acetal was isolated by washing the reaction mixture first with sodium hydroxide solution and then with water, drying the organic phase and removing the solvent in vacuo. The resulting residue was a dark brown oil weighing 6.8 g (corresponding to 42 per cent of the 25

theoretical yield), n D 1.4625.

Example 5.

Preparation of acetaldehyde-bis-(2,2-dinitropropyl)-acetal.

16 g (0.10 M, 96% pure) of 2,2-dinitropropanol, 4 g of powdered calcium chloride and 2.2 g (0.050 M) of acetaldehyde were introduced into a glass pressure vessel placed in ice. The container was then closed with a rubber stopper which was held in place by mechanical means to prevent loss of acetaldehyde by evaporation. The mixture was first shaken vigorously and then shaken approx. twice a day for the following 6 days, as it was kept at room temperature. The contents of the flask were then poured into ice water containing 1.6 g of sodium hydroxide. The crude product was separated using methylene chloride. The organic solution was extracted first with 20 ml of 1N sodium hydroxide solution, then with 40 ml of 10% sodium bisulphite solution which had previously been neutralized with sodium carbonate, and finally twice with water. The extract was dried and the solvent removed in vacuo. The viscous, light green residue thus obtained weighed 3.9 g, n D 1.4588. Distillation in vacuum gave a temperature of 110-165° C under a pressure of 0.45 mm Hg, as well as a clear yellow residue weighing 2.6 g (corresponding to 16 per cent of the theoretical yield).

25 n D 1.4609. By distilling part of this residue from a flask tube at a pressure of 0.3-0.4 mm Hg in an oil bath at a temperature of 170-190° C, an almost colorless liquid was obtained, n D 1.4607 . The spectrum of this product in the infrared region was identical to the spectrum of an authentic sample of acetaldehyde bis-(2,2-dinitropropyl) acetal.

Example 6.

Preparation of acetone-bis-(2-nitrobutyl)-acetal.

This compound was prepared by proceeding as indicated in example 5 by reacting acetone with 2-nitrobutanol in the presence of ferric chloride as a catalyst.

Example 7.

Preparation of n-butyraldehyde-bis-(2-chloro-2,4,4-trinitro-1-butyl)-acetal.

n-Butyraldehyde-bis-(2-chloro-2,4,4-tri-nitro-1-butyl)-acetal was prepared by proceeding as indicated in Example 5 by reacting n-butylaldehyde with 2-chloro-2 ,4,4-trinitro-l-butanol in the presence of p-toluenesulfonic acid as a catalyst.

Example 8.

Preparation of methyl-n-butyl-ketone-bis-(5,5-dinitro-5-phenyl-l-pentyl)-acetal.

This compound was prepared by proceeding as indicated in the previous examples by reacting methyl-n-butyl ketone with 5,5-dinitro-5-phenyl-1-pentanol in the presence of m-benzene-disulfonic acid as a catalyst.

Example 9.

Preparation of ethyl isopropyl ketone bis (2-nitro-4-phenyl-2-n-propyl-phenyl-1-butyl)-acetal.

The above compound was prepared by proceeding as described in the previous examples and reacting ethyl isopropyl ketone with 2-nitro-4-phenyl-2-n-propylphenyl-1-butanol 1 in the presence of zinc chloride as catalyst.

Example 10:

Preparation of formaldehyde-bis-(3- nitro- 3- cyclohexyl- 5- bromo- l- pentyl)- acetal.

The above compound was prepared by proceeding as indicated in the preceding examples and reacting formaldehyde or a formaldehyde polymer with 3-nitro-3-cyclohexyl-5-bromo-1-pentanol.

Example 11.

Preparation of propionaldehyde bis-(7-aza-5,5,7-trinitro-3-octyl)-acetal.

The above compound was prepared by proceeding as described in the previous examples and reacting propionaldehyde with 7-aza-5,5,7-trinitro-3-octanol.

Example 12.

Preparation of acetaldehyde bis-(2, 2, 2- trinitroethyl) acetal.

The above compound was prepared by proceeding as described in the previous examples and reacting acetaldehyde with 2,2,2-trinitroethanol.

Example 13.

Preparation of acetaldehyde-bis-(2,2,4,4-tetra-nitro-n-pentyl)-acetal.

The above compound was prepared by proceeding as described in the preceding examples and reacting acetaldehyde with 2,2,4,4-tetranitro-n-pentanol.

The (3-nitroalcohols used as starting materials in the process according to the invention are produced by reacting the corresponding a-nitroalkanes with formaldehyde using the well-known Henry reaction. The (3-gem-dinitroalcohol reaction components such as . 2,2-dinitroetha-hol, is preferably prepared by acidifying the corresponding alkali metal salts in accordance with the method described by Duden and Pondorff in Ber., 38, 2031 (1905). 2,2,4,4-tetranitrobutanol can is prepared by acidifying a salt of dinitroethanol so that the salt of 2,2,4,4-tetranitrobutanol is formed From the latter compound the free alcohol is prepared by adding acid.

The primary nitroalkanols other than 3-nitroalcohols which are suitable as reaction components in the process according to the invention are prepared by reducing their corresponding acid halides with sodium borohydride. The 4,4-dinitro-1-alcohol reaction components for the method can be prepared by selective reduction of Michael adducts to 1,1-dlnitroalkanes which are then reduced to the desired dinitroalcohols. This method is described in more detail by Shechter, et al., J. Am. Chem. Soc, 74, 3664 (1952) and Feuer et al, J. Am. Chem. Soc, 77, 5740 (1955). 3,3-dinitro-1-alkanols can be prepared by reacting the corresponding primary amines with nitric acid, whereby unstable di-azo compounds are formed which can be split into the desired alcohols with the evolution of gaseous nitrogen, as described in more detail by Herzog et al., in J. Org. Chem., 23, 1809 (1958).

The reaction components in the process according to the invention, which consist of secondary nitroalkanols, are produced by selective reduction of ketones with sodium borohydride. These ketones are obtained by the well-known Michael addition of alkyl-vinyl ketones such as methyl-vinyl ketone to active hydrogen compounds, thus as fully described on page 484 of "Advanced Organic Chemistry" by Fuson, John Wiley & Sons, Inc. ( 1950).

It is obvious that a large number of different acetals can be prepared by

using the method according to the invention using starting materials in accordance with the desired products.

Mixtures of the aforementioned reaction components can be used in the method according to the invention. It is thus within the scope of the invention to prepare acetals with alkoxy groups. Thus, one can e.g. react an aldehyde or ketone as acetaldehyde with a mixture of nitroalcohols such as a mixture of 2,2,2-trinitroethanol and 2-chloro-2-nitroethanol, whereby a product with a mixed alkoxy group such as e.g. acetaldehyde-2,2,2-trinitroethyl-2-chloro-2-nitroethyl acetal.

It will be understood that the new nitroacetals which are produced by the process according to the invention are either acetals or ketals, depending on the meaning of the symbols R and R-, in the above general formula. However, all these new compounds are generally designated as acetals in accordance with the terminology normally used in the literature. This

terminology is recognized by and used

of Chemical Abstracts as it appears from

Section 299 in a publication entitled

“The Naming and Indexing of Chemicals

Compounds by Chemical Abstracts».

Claims (4)

1. Method for the production of nitroacetals which are usable as plasticizers in the manufacture of polymers and which have the general formula: characterized by reacting a compound with the general formula: which is either added beforehand to the reaction mixture or which is formed in situ, with a nitro alcohol corresponding to the general formula: wherein in the above general formula R and R denote hydrogen or an alkyl radical, R2 and R3 denote hydrogen or halogen, or an alkyl, nitroalkyl, nitro, aryl, alkaryl, arylalkyl, cycloalkyl, haloalkyl or nitroza -alkyl radical, while A denotes an alkylene radical. 2. Process according to claim 1, characterized in that the reaction is carried out in the presence of an acidic esterification catalyst. 3. Method according to claim 1, characterized in that acetaldehyde is reacted with 2,2-dinitropropanol in the presence of sulfuric acid as a catalyst. 4. Method according to claim 1, characterized in that formaldehyde is reacted with 2,2-dinitropropanol in the presence of sulfuric acid as a catalyst.