JP2857402B2 - Method for preparing 2-phenyl-1,3-propanediol dicarbamate - Google Patents

Description

The present invention relates to a novel method for preparing or synthesizing 2-phenyl-1,3-propanediol dicarbamate.

[Conventional technology]

The synthesis of 2-phenyl-1,3-propanediol dicarbamate was carried out by the method described in U.S. Pat. No. 2,884,444, ie by the following urethane exchange method: Alternatively, the compound is 2-phenyl-1,3-
It is also prepared by reacting propanediol with phosgene to form the corresponding dichlorocarbonate derivative and converting it to a dicarbamate by ammoniation.

[Problems to be solved by the invention]

The process described in the above patents has a number of disadvantages, for which the inventors and chemical manufacturers have spent considerable time and money improving this synthesis, all of which have been successful until the present invention. Did not.

The main disadvantages of the process disclosed in US Patent No. 2,884,444 are as follows: 2-phenyl-1,3, the starting material used for the synthesis is obtained by reduction of diethylphenyl malonate with lithium aluminum hydride -Propanediol. Diethyl phenyl malonate is a relatively expensive raw material, and the reduction method using lithium aluminum hydride is costly and dangerous, and the production volume on the order of tons is not preferable.

[Means for solving the problem]

The route to 2-phenyl-1,3-propanediol dicarbamate disclosed herein has been found to be an economical and low-risk method that can be easily transferred to industrial operations.

Example 1 describes the preparation of benzaldehyde oxime. In this case, the reaction to produce benzaldehyde oxime by reacting hydroxylamine sulfate or hydroxylamine hydrochloride with benzaldehyde was optimized to yield greater than 95% and adapted for mass production.

Example 2 illustrates the preparation of nitromethylbenzene by the oxidation of benzaldehyde oxime under controlled conditions to give a high purity product in high yield.

It has already been proposed to prepare nitromethylbenzene by reacting a benzyl halide with silver nitrite or sodium nitrite in dimethyl sulfoxide. Such a process is expensive and gives relatively low yield and low purity products. In addition, the use of dimethyl sulfoxide raises environmental concerns. Furthermore, it has been proposed to prepare nitromethylbenzene by oxidizing benzaldehyde oxime with trifluoroacetic acid and a phosphate buffer. This method is also expensive and the yield is low.

According to the invention, the oxidation of benzaldehyde oxime is
Using about 30% or 50% hydrogen peroxide or preferably 35% peracetic acid in commercially available acetic acid as an oxidizing agent,
Achieved at a controlled temperature of 90 °, yielding high yield and high purity of nitromethylbenzene.

Example 3 shows the subsequent reaction of nitromethylbenzene with formaldehyde to give 2-nitro-2-phenyl-1,
The reaction for obtaining 3-propanediol will be described.

The literature preparation of nitrodiols involves the reaction of nitromethylbenzene with formaldehyde, but according to the present invention, the reaction is carried out in that sodium bicarbonate or sodium carbonate is used as a catalyst instead of the conventionally preferred sodium hydroxide. Has been improved. This change in the catalyst made it easier to control the addition of the nitro compound to formaldehyde, and reduced the amount of polymeric substances produced by side reactions.

The most critical feature of the synthesis method of the present invention is the removal of the aliphatic nitro group from 2-nitro-2-phenyl-1,3-propanediol found in Example 4.

Prior to the present invention, there was no known method for simply removing aliphatic nitro groups from a molecule. Prior art methods have been used to convert tertiary nitro compounds to tributyltin hydride.
de). This reagent is very expensive and not suitable for mass production. Another proposed method is the hydrogenation of benzyl nitro compounds with palladium on charcoal at 1200 psi. However, there is no information that debenzylation occurred and the desired product was obtained when the reaction was carried out at 1200 psi. When the reaction was run at 50 psi with palladium on charcoal, a mixture was formed containing the debenzylated amino compound in such an amount that industrial application of the reaction was not possible. In accordance with the present invention, it has been discovered that removal of the aliphatic nitro group is accomplished by hydrogenation of 2-nitro-2-phenyl-1,3-propanediol in the presence of palladium on calcium carbonate at 50 psi. This method allows the production of highly pure 2-phenyl-1,3-propanediol with a yield of about 80%. This method allows for large-scale hydrogenation in a standard reactor that withstands 125 psi.

The final reaction of the synthesis method of the present invention is 2-phenyl-1,3
-Conversion of propanediol to the desired dicarbamate, as described in Example 5.

The use of phosgene to convert diols to dicarbamates is known in the prior art. However, such prior art methods require the presence of an acid acceptor such as dimethylaniline or antipyrine. According to the present invention, the prior art acid acceptor is replaced with an ether such as ethyl ether or tetrahydrofuran, so that the reaction can be carried out in solution without the need for separation of a precipitate or recovery or purification of the acid acceptor.

The method of the present invention is quantitative and eliminates contamination of the end product. Further, chlorocarbonate (chlorocarbonat)
The solution of e) can be easily pressed into ammonium hydroxide,
Since the removal of the organic solvent can be easily achieved by distillation under reduced pressure, this synthesis can be easily applied on an industrial scale.

〔Example〕

The following non-limiting examples will illustrate the novel synthesis in their preferred embodiments to further illustrate the synthesis of the present invention.

Example 1 Benzaldehyde oxime 943 g (5.75 mol) of hydroxylamine sulfate is placed in a 12 liter flask containing 1160 g (11 mol) of benzaldehyde, 250 ml of methanol and 5900 ml of water. The mixture is stirred in an ice bath and cooled to 10 ° C. While maintaining the temperature of the mixture below 25 ° C by cooling, 960 g (12
Mol) of 50% sodium hydroxide is slowly added to the mixture over 1 hour. The mixture is stirred until the reaction is complete (about 1 hour). The mixture is neutralized with acetic acid to pH 7.0. Separate the lower layer of oxime and extract the aqueous layer with 2 liters of toluene. The oxime layer and the toluene extract are washed twice with 1 liter of water. Toluene is distilled off (Strip) and the purity is 98%
Of oxime are obtained in a yield of 95%.

Example 2 Nitromethylbenzene 184.1 g (1.51 mol) of benzaldehyde oxime and 185 ml of glacial acetic acid are placed in a 3-liter three-necked flask. The mixture is stirred and heated to 80 ° C. A solution of 344.1 g (1.65 mol) of 36.6% peracetic acid and 19 g of sodium acetate trihydrate is added at such a rate that the temperature is maintained between about 80 ° C and about 90 ° C. About 3 at 85 ° C until the oxime is gone
-Continue stirring for 1/2 hour. Cool the reaction mixture to 25 ° C,
One liter of water is added and the mixture is stirred well and the resulting oil layer is separated. The aqueous layer is extracted twice with 200 ml of methylene chloride. Combine the aqueous extract with the oil layer and add 2
Wash once with 600 ml of 5% sodium bicarbonate solution, wash once more with 400 ml of water, dry over sodium sulfate and concentrate to give a pale orange oil. The yield is 173.5 g (84%) of 97% pure material by GC.

Example 3 2-nitro-2-phenyl-1,3-propanediol 100 g (0.73 mol) of nitromethylbenzene, 131.5 g
(1.61 mol) of 37% formaldehyde and 1.8 g of sodium carbonate monohydrate in 500 ml with a mechanical stirrer
Into a beaker. The mixture is stirred and kept at 38 ° C using a cold water bath once the temperature has risen to 38 ° C. After 1-1 / 2 hours,
Crystals begin to form. Lighten the mixture with 210 ml of ice water 10
Stir at C for about 2 hours. The mixture is filtered and the filtrate is washed with water. Return the wet cake to the beaker and add 280 ml of ice water. The mixture is stirred for 1 hour, filtered and air-dried overnight. The solid is stirred with 250 ml of toluene for about 1 hour at 10 ° C., filtered and then washed with cold toluene and dried. The yield is 112.6 g of nitrophenyldiol (78%), mp: 96-97.5 ° C.

Example 4 2-phenyl-1,3-propanediol 12 g (0.006 mol) of 2-nitro-2-phenyl-1,3
-Propanediol, 400 mg of 5% palladium on calcium carbonate and 150 ml of methanol are placed in a Parr hydrogenation bottle and reduced with hydrogen overnight. The mixture is filtered over celite, concentrated to an oil and recrystallized from 30 ml of toluene. The yield is 7.4 g (80%) of product, mp: 52-4 ° C.

Example 5 2-Phenyl-1,3-propanediol-dicarbamate 30.4 g (0.2 mol) of 2-phenyl-1,3-propanediol are dissolved in 100 ml of toluene and 35 g of tetrahydrofuran at room temperature. 30ml while keeping the temperature below 25 ° C
Phosgene (0.44 mol) is passed through the solution. After the phosgene addition, the solution is stirred for about 1 hour at room temperature. The tetrahydrofuran solution is added dropwise to 140 ml of concentrated NH ₄ OH kept at 0 ° C. Add 100 ml of water to improve stirring. Stirring is continued at room temperature for 1-1 / 2 hours and concentrated in vacuo on a steam bath to remove most of the tetrahydrofuran. 150 ml of water are added and the mixture is stirred for 1 hour at room temperature. The mixture is filtered, the filtrate is washed with water and dried at 50 ° C. in vacuo. Yield of crude W-554 46 g (96.6%)
(Melting point: 149-151 ° C). Recrystallization from 450 ml of methanol gives 36 g of W-554 (75.6%). It should be understood that the above examples illustrate the best aspects of the present invention. It is anticipated that one skilled in the art will make many variations upon this disclosure. Modifications, substitutions, and permissible ranges of variation are contemplated, and in some cases certain features of the invention may be used without a corresponding use of other features. Accordingly, the spirit and scope of the invention disclosed herein should be limited only by the following claims.

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Claims (5)

(57) [Claims] A) reacting a compound selected from the group consisting of hydroxylamine sulfate and hydroxylamine hydrochloride with benzaldehyde to produce benzaldehyde oxime; b) oxidizing the benzaldehyde oxime of step a to obtain nitromethylbenzene C) reacting the nitromethylbenzene obtained in step b with formaldehyde to give 2-nitro-2-phenyl-1,
Producing 3-propanediol; d) reducing 2-nitro-2-phenyl-1,3-propanediol with hydrogen to produce 2-phenyl-1,3-propanediol; e) 2-phenyl- 1,3-Propanediol is converted to 2-phenyl-1,3 by phosgenation and ammoniation.
The method comprises the steps of converting into 2-propanediol / dicarbamate, wherein the 2-phenyl-1,3-propanediol / dicarbamate obtained in step e is a carbamate that is not a substituted carbamate. Wherein the conversion of 2-phenyl-1,3-propanediol to 2-phenyl-1,3-propanediol dicarbamate in step e) comprises converting an ether selected from the group consisting of ethyl ether and tetrahydrofuran to A method for preparing 2-phenyl-1,3-propanediol dicarbamate, which is performed in a solution containing the compound. 2. The method according to claim 1, wherein said compound is hydroxylamine sulfate. 3. The method according to claim 1, wherein said compound is hydroxylamine hydrochloride. 4. The process according to claim 1, wherein the reduction of 2-nitro-2-phenyl-1,3-propanediol is carried out in the presence of a catalyst for palladium on calcium carbonate. 5. The method according to claim 1, wherein said solution is a solution of tetrahydrofuran and toluene.