JPH061756A - Production of 1,3-propandiol derivative - Google Patents

Abstract

PURPOSE:To obtain high-purity 2-bromo-2-nitro-1,3-propandiol in high yield by using inexpensive and readily available 2-hydroxymethyl-2-nitro-1,3-propandiol and nitromethane at a relatively low cost as raw materials. CONSTITUTION:A solution containing 2-hydroxymethyl-2-nitro-1,3-propandiol and nitromethane in a molar amount of >0.6 based thereon is brominated in the presence of an alkali to afford the objective 2-bromo-2-nitro-1,3-propandiol.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 2-hydroxymethyl-
Starting from 2-nitro-1,3-propanediol and nitromethane, high quality 2-bromo-2-nitro-
The present invention relates to a method for producing 1,3-propanediol in high yield. 2-Bromo-2-nitro-1,3-propanediol is currently used in various industrial drugs under the name Pronopol. The usefulness of this compound can be seen from the fact that many process patent applications have been filed as shown below.

[0002]

2. Description of the Related Art As a method for producing 2-bromo-2-nitro-1,3-propanediol, a method is known in which nitromethane and formaldehyde are subjected to an addition reaction and then the product is brominated. Specifically, 1) a method in which nitromethane and formaldehyde are subjected to an addition reaction in anhydrous alcohol in the presence of an alkali metal alcoholate to separate the resulting alkali salt of nitroalcohol, followed by bromination in a nonpolar solvent [Hemische. 56, 611 (19).
23)]. 2) A method in which nitromethane and formaldehyde are added in an aqueous solution in the presence of an alkaline earth metal salt compound and an alkaline earth metal hydroxide to brominate the resulting metal salt of nitroalcohol without separation (West German Patent Application Publication Nos. 1768976 and 1804068). 3) A method in which nitromethane and formaldehyde are added in an aqueous solution in the presence of an alkaline earth metal hydroxide and then brominated (JP-A-48-72108). 4) A method in which nitromethane and formaldehyde are added in an aqueous solution in the presence of a stoichiometric amount of alkali hydroxide and then brominated (JP-B-49-20761 and JP-B-50-
7577 publication). 5) When adding nitromethane and formaldehyde in the presence of an alkaline earth metal chloride and an alkaline earth metal hydroxide, the amount of alkali or alkaline earth metal hydroxide is 1.3 to 1.4 mol. Is used excessively in the range of 2) to suppress the formation of a by-product having a large number of aldehyde bonds, that is, 2-hydroxymethyl-2-nitro-1,3-propanediol (JP-A-49-70911). 6) A method in which nitromethane and formaldehyde are added in the presence of alkali carbonate and then brominated (JP-A-52-
No. 3011). 7) A method in which nitromethane and formaldehyde are added in the presence of alkali in hydrous methanol or hydrous ethanol and then brominated (JP-A-57-2242). 8) A method in which nitromethane and formaldehyde are added in the presence of an alkali using an alkane polyol as a solvent and then brominated (JP-A-56-113745). 9) A method of brominating a nitroalcohol compound to which nitromethane and formaldehyde have been added with brominated chlorine or bromine and chlorine (Polish Patent No. 100819 and Czechoslovakian Patent No. 243669).

2-hydroxymethyl-2-nitro-1,
As a method for producing 3-propanediol, 10) 2-hydroxymethyl-2-nitro-1,3-propanediol is reacted with a ketone or an aldehyde to produce a ring-closed dioxane, and hydroxymethyl is further added. A method of converting a group into bromine and then ring-opening with an acid (US Pat. No. 4,851,588). 11) brominating 2-hydroxymethyl-2-nitro-1,3-propanediol in the presence of potassium hydroxide,
It is known that 2-bromo-2-nitro-1,3-propanediol is by-produced when a potassium salt of 2-bromo-2,2-dinitromethane is produced (Hemische.
Berichte 57B, 2127 (1924)). 12) In the above reaction 5), 2-hydroxymethyl-2-nitro-1,3-propanediol is produced as a by-product, which is further brominated in the presence of excess alkali to give 2-bromo- It has been suggested that 2-nitro-1,3-propanediol can be produced (JP-A-49-70911).

As still another production method, there is known 13) a method in which nitromethane is brominated and then reacted with formaldehyde (JP-A-1-132549).

[0005]

Although many production methods have been proposed as described above, the addition reaction of nitromethane and formaldehyde occurs extremely rapidly in the presence of a base, and the reaction heat is more violent. However, the current situation is that the problem of reaction control arises when it is carried out industrially on a large scale. In addition, the method of brominating nitromethane causes a problem in the quality of the final product due to the mixture of dibromo compounds and tribromo compounds. 2-hydroxylmethyl-2-nitro-1,3
In the reaction using propanediol as a raw material, the reaction via the dioxane intermediate has a large number of steps and is industrially unsuitable. In addition, when an excess amount of alkali is used, the quality of the product is poor because the product is unstable to alkali. In addition, the inclusion of formaldehyde, which is a by-product, also causes deterioration of quality. As described above, the conventional manufacturing method is not always satisfactory as a method for industrially performing it on a large scale.

[0006]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors to solve the above-mentioned problems in industrial implementation, 2-hydroxylmethyl-2-nitro-1,3 was obtained.
-By brominating a mixed solution of propanediol and nitromethane as a starting material in the presence of an alkali, it was found that highly pure 2-bromo-2-nitro-1,3-propanediol can be obtained in a high yield, The present invention has been completed based on this finding.

That is, according to the present invention, 2-hydroxymethyl-2-nitro-1,3-propanediol is added to
A method for producing a 1,3-propanediol derivative, which comprises brominating a liquid containing 6 times or less mole of nitromethane in the presence of an alkali to obtain 2-bromo-2-nitro-1,3-propanediol. It is provided. The reaction of the present invention is represented by the following formula.

[0008]

[Chemical 1]

That is, in the theoretical amount, 1 mol of nitromethane, 3 mol of bromine and 3 mol of alkali are used for 2 mol of 2-hydroxylmethyl-2-nitro-1,3-propanediol.
Used in molar proportions. 2-bromo-2 of the desired product
This means that 3 mol of -nitro-1,3-propanediol is produced. In the actual reaction, each component is 90
It can be used within the range of 110%. The preferred reaction molar ratio is 2-hydroxylmethyl-2-nitro-
Nitromethane is 0.45 to 0.55 mol and bromine is 1.35 to 1.65 per 1 mol of 1,3-propanediol.
Molar and alkali are 1.35 to 1.65 mol.

In the embodiment of the method of the present invention, the operation is usually 2
Done in steps. In the first stage, 2-hydroxylmethyl-
An alkali is added to a mixed solution of 2-nitro-1,3-propanediol and nitromethane. This first-stage operation is a salt-forming treatment, in which 2-hydroxylmethyl-2-nitro-1,3-propanediol and nitromethane are added to a water-alcohol mixed solvent, and then alkali metal or alkaline earth metal water is added. This is done by adding an oxide. The hydroxide is specifically sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide or the like. Water-soluble ones are added in the form of an aqueous solution, and sparingly soluble ones are added little by little. Methanol and ethanol are used as the alcohol of the alcohol-based mixed solvent.
The alcohol concentration is 10 to 90%, preferably 30 to
50%. The temperature of the first stage operation is -10 to 50 ° C,
It is preferably 0 to 10 ° C.

Next, bromination is carried out as a second stage operation. This reaction can be carried out in one pot by adding bromine as it is without isolating the product from the reaction liquid of the first stage. Second stage bromination reaction temperature is -10
It is 50 ° C, preferably 0 to 10 ° C. In this reaction, when the amount of nitromethane is small and the amount of bromine is excessive, 2,2-dibromo-2-nitroethanol, which is a further brominated 2-bromo-2-nitro-1,3-propanediol, is by-produced, 2 if excess nitromethane and low bromine
The yield of -bromo-2-nitro-1,3-propanediol decreases.

In the reaction of the present invention, the formaldehyde produced by the bromination of 2-hydroxylmethyl-2-nitro-1,3-propanediol is captured by nitromethane, which is also the desired product, 2-bromo. Converted to 2-nitro-1,3-propanediol. Therefore, formaldehyde, which is a by-product, is effectively used, and highly pure 2-bromo-2-nitro-1,3-propanediol is obtained. Further, the reaction of the present invention is not as vigorous as the reaction of nitromethane and formalin with alkali, and therefore the reaction can be easily controlled by adjusting the addition rate of bromine and the like. When the theoretical amounts of alkali and brominating agent are used, the reaction solution becomes almost neutral at the end of the reaction. However, when the reaction is alkaline and the reaction is completed by the use of an alkali and a brominating agent, it is necessary to further add an inorganic acid for neutralization. Examples of the inorganic acid include hydrochloric acid, sulfuric acid and phosphoric acid. From the reaction solution thus obtained, 2-bromo-2-nitro-1,
3-Propanediol can be isolated. That is, the reaction solution is concentrated to a volume of 10 to 25%, and after cooling, the crystals are collected by filtration and dried to obtain 2-bromo-2-nitro-1,3-propanediol with high yield and high purity. it can.

[0013]

EXAMPLES Next, the present invention will be described in more detail based on examples. In this example, the purity was measured by gas chromatography. Conditions for gas chromatography Device: Gas chromatograph with FID detector Column: Glass column length 1.5M Filler: Liquid phase Silicon GE-XE60 3% Carrier Chromosolve WAW-DMGS 60-80me
sh Column bath temperature: 140 ℃ Carrier gas: Nitrogen 55ml / min

Example 1 151.0 g (0.5 mol) of a 50% aqueous solution of 2-hydroxylmethyl-2-nitro-1,3-propanediol
And 15.3 g (0.25 mol) of nitromethane were added to a mixed solution of 100 g of methanol and 45 g of water, and 48% aqueous sodium hydroxide solution 61.3 was added at 5 to 10 ° C. under ice cooling.
g (0.74 mol) was added dropwise. After the addition was completed, the mixture was stirred at the same temperature for 1 hour, and then 118.4 g (0.74 mol) of bromine was added.
Was added dropwise at 0 to 5 ° C. The mixture was stirred again at the same temperature for 1 hour. Thereafter, the pH was adjusted to 1 with concentrated hydrochloric acid, and concentrated under reduced pressure to about 1/5 volume. The solution was cooled, and the crystals were collected by filtration and dried to give 2-bromo-2-nitro-1,3-propanediol as white crystals having a melting point of 130 to 130.5 ° C, 89.6 g (purity 99.2%, yield). Rate 89.3%).

Example 2 75.5 g (0.25 mol) of a 50% aqueous solution of 2-hydroxylmethyl-2-nitro-1,3-propanediol
And nitromethane (7.6 g, 0.125 mol) were added to a mixed solution of ethanol (40 g) and water (40 g).
At -15 ° C, 14.1 g (0.19 mol) of calcium hydroxide was added in small portions. Further, the mixture was stirred at the same temperature for 2 hours, and then 60.0 g (0.375 mol) of bromine was added to 0 to 5
It was added dropwise at ° C. The mixture was stirred again at the same temperature for 1 hour. Thereafter, the same treatment as in Example 1 is carried out and 2-bromo-2-nitro-
61.2 g of 1,3-propanediol as white crystals
(Purity 99.0%, yield 81.0%) was obtained.

Comparative Example 1 75.5 g (0.25 mol) of a 50% aqueous solution of 2-hydroxylmethyl-2-nitro-1,3-propanediol
150 g of water was added thereto, and 88.6 g (0.79 mol) of 50% potassium hydroxide was added little by little at 0 to 5 ° C under ice cooling. Further, the mixture was stirred at the same temperature for 2 hours, then bromine 125 g
(0.78 mol) was added dropwise at 0 to 5 ° C. The mixture was stirred again at the same temperature for 1 hour. The reaction solution was extracted twice with 100 ml of toluene, and the solvent was distilled off under reduced pressure to obtain 62 g of oil. This oil contains 2-bromo-2-nitro-1,3
-Propanediol was not found. Furthermore, 0.4 g (yield 0.7%) of 2-bromo-2 was added to the aqueous layer after extraction.
Only -nitro-1,3-propanediol was detected. (Chemische Berichte 57B, 2127 (1
924) additional test).

[0017]

According to the method of the present invention, 2-hydroxylmethyl-2-nitro-1,3-propanediol and nitromethane, which are relatively inexpensive and easily available, are used as the starting materials in high yield and high yield. Pure 2-bromo-2-nitro-
1,3-Propanediol can be obtained. Also,
The reaction does not proceed rapidly and can be easily controlled by the rate of addition of the drug, etc., which is extremely suitable as a method for carrying out on a large scale industrially.

Claims (1)

[Claims] 1. 2-Hydroxymethyl-2-nitro-
A liquid containing 0.6 mol or less of nitromethane with respect to 1,3-propanediol is brominated in the presence of an alkali to obtain 2-bromo-2-nitro-1,3-propanediol. Process for producing 1,3-propanediol derivative.