JPS598256B2 - Method for producing p-nitrophenyl chloroformate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing p-nitrophenyl chloroformate represented by the general formula o2N°OΠCl (wherein X represents hydrogen, a nitro group, or a . . . rogen atom).

p-Nitrophenyl chloroformate is useful as a starting material for p-nitrophenyl tertiary-butyl carbonate, which is a tertiary-butyloxycarbonyl reagent for amino-protecting groups, in the pharmaceutical and peptide synthesis fields, and as an intermediate. It is.

Conventional methods for reacting this type of p-nitrophenol with phosgene include reacting the Na salt of p-nitrophenol with phosgene, or reacting p-nitrophenol with phosgene in the presence of a tertiary amine such as quinoline. Method of reacting with phosgene [German Patent No. 287805, J, A, C
, S796180 (1957) etc.] C of substituted phenol
Method of reacting a salt with phosgene (Japanese Patent Publication No. 43-21
No. 2) etc. are known. In these prior art (
l) In the method of reacting the Na salt of anhydrous p-nitrophenol with phosgene in toluene or benzene, the carbonic acid diester of p-nitrophenol is produced as a by-product even at relatively low temperatures, and the purity and yield of the target chloroformate are reduced. decrease.

(;i) There are many problems in industrially producing Na of anhydrous p-nitrophenol. For example, p-nitrophenol-Na salt is commercially available in a state containing two molecules of water of crystallization, and dehydration to form anhydrous p-nitrophenol-Na salt requires high temperatures, which is dangerous and Anhydrous materials are difficult to handle because they are hygroscopic. Also Ca
A similar problem exists with salt. (;Ii) The method of reacting p-nitrophenol with phosgene using an aliphatic tertiary amine as an acid acceptor is generally difficult to recover the amine, and even under appropriate conditions, nitro The disadvantages were that a large amount of carbonic acid diester of phenol was produced as a by-product, and the desired p-nitrophenyl chloroformate was not obtained at all or only in a very small amount. The present invention was made in view of the above-mentioned current situation, and its purpose is to use an acid acceptor that is immiscible with water and easy to recover, and to achieve high purity and high yield without the by-product of carbonic acid diester of p-nitrophenol. p-
An object of the present invention is to provide a method for producing nitrophenyl chloroformate.

According to the present invention, the above object is achieved by using N- as an acid acceptor.
This was achieved by using N-diethylaniline.

That is, the present invention provides for the preparation of N-N-diethylaniline by dissolving or suspending p-nitrophenol represented by the general formula (wherein X represents hydrogen, a nitro group, or... rogen atom) in an organic inert solvent. A general formula characterized by reacting with phosgene in the presence of
has the same meaning as above).

To summarize the present invention, the chemical reaction in the present invention is as follows, and the starting materials are p-nitrophenol, 2-chloro-4-nitrophenol, 2,4-dinitrophenol, etc.

This starting material is dissolved or suspended in an organic solvent such as benzene, toluene, xylene, chlorobenzene, or tetrahydrofuran, but it is desirable to use an organic solvent that is immiscible with water in the process of purifying the target product. Phosgene is dissolved in a solvent and reacted with p-nitrophenol. At this time, N.N-diethylaniline is used as the base in the above reaction formula. As is clear from the reference examples described later, N-N-diethylaniline is more specific in its action as an acid acceptor than the heterocyclic tertiary amine and its cognate N-N-dimethylaniline, and at the same time, it is a fatty acid acceptor. Family 3rd
It does not have the disadvantages of grade amines. In order to specifically explain this, a reference example based on a conventional method will be shown. Reference example 1 p-nitrophenol 8.0y (0.0435 mol)
, toluene 35mi, phosgene 5.4V (0.055
pyridine 3.8y (0.047 mol)
A solution of 5 ml of toluene (8 mol) was added dropwise at 4 to 5°C, and after the dropwise addition was completed, the mixture was stirred at 20°C for 3 hours, and the precipitated hydrochloride crystals were dissolved and separated in water.

Product 8.37 obtained from the water-insoluble matter and toluene layer was p-nitrophenyl carbonic diester, and the production rate reached 96.8%, and no chloroformate was obtained.

Reference example 2 A mixture of 307 d of p-nitrophenol, 160 d of toluene, 277 d of phosgene, 22.27 d of vicolin, and 2 d of toluene.
0 ml of the solution was added dropwise over 40 minutes at 3 to 13°C, and after the dropwise addition was completed, the reaction was completed by stirring at 30°C for 2 hours.

As a result of treatment in the same manner as in Reference Example 1, the yield of p-nitrophenyl chloroformate was 49%.

Reference Example 3 Similar to Reference Example 2, using quinoline instead of picoline.
The yield of p-nitrophenyl chloroformate obtained using 7y was 41.8%.

Reference example 4 p-nitrophenol 307, tetrahydrofuran 15
0 ml of a solution of phosgene 297 at O~5°C.
Dimethylaniline 31.57, Tetrahydrofuran 20
A solution of m1 was added dropwise over 40 minutes, and after the addition was completed, the mixture was stirred at 30°C for 2 hours.

The treatment was carried out in the same manner as in Reference Example 1, and the target p-nitrophenyl chloroformate was obtained in a yield of 61.8% (based on p-nitrophenol). As is clear from these reference examples, p
- In a reaction format in which nitrophenol is reacted with phosgene, either a heterocyclic tertiary amine or N/N-dimethylaniline, which is a typical example of an aromatic tertiary amine, is used as the acid acceptor. It was also observed that the yield of chloroformate was extremely low;
When N-N-diethylaniline of the present invention is used, the yield is 90% or more as shown in the Examples, and its specificity is recognized.

Next, the present invention will be described with reference to Examples, but the present invention is not limited thereto in any way.

Example 1 p-Nitrophenol 607 (0.431 mono(he), toluene 260ml, phosgene 50.5y(
A solution of NN-diethylaniline 72.1V (purity 98%, 0.474 mol) and 40 ml of toluene was added dropwise to the mixture of 0.510 mono(h) at -2 to 5°C over a period of 1 hour.

After the dropwise addition was completed, the mixture was stirred at 18 to 20°C for 2 hours to complete the reaction. After adding water to dissolve and separate the precipitated hydrochloride, the toluene layer was washed with HCl water and then with water, then dehydrated, and the toluene was distilled off.
3.47 (yield 96%) was obtained. Example 2 N-N-diethylaniline 2 was added to a mixture of p-nitrophenol 21k9, toluene 871 and phosgene 18k9.
4.8k9 and toluene 151? A solution of 2 at 4-8℃
It takes a while to drip, and after the dripping is finished, the temperature is 2.5 to 18-20℃.
The reaction was completed by stirring for an hour.

After distilling off phosgene under reduced pressure at 40°C or lower, Example 1
29.4 kg (yield: 96.6%) of p-nitrophenyl chloroformate was obtained.

As described above, the present invention solves problems related to dehydration and handling of raw materials during industrialization by using free p-nitrophenol in place of Na salt in the conventional method, and also provides a water-insoluble aromatic compound with low odor. The use of tertiary amines is particularly effective in that it improves the working environment, facilitates the recovery of amines, and eliminates the need for waste water treatment.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, X represents hydrogen, a nitro group, or a halogen atom)
General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( A method for producing p-nitrophenyl chloroformate represented by the formula (wherein X has the same meaning as above).