JPH02129151A - Production method of chloroformic acid (9-fluorenylmethyl) - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a protective reagent for amino acids, peptides, etc., in good yield for a short time by reacting 9- fluorenylmethanol with phosgene in the presence of tertiary phosphines. CONSTITUTION:9-Fluorenylmethanol is reacted with phosgene in a solvent, such as dichloromethane, using tertiary phosphines (e.g., tributylphosphine) expressed by the formula R<1>R<2>R<3>P (R<1> to R<3> are alkyl, aralkyl, aryl or at least two of the R<1> to R<3> are mutually connected bi- or tri-valent cyclic hydrocarbon) at -78 to +40 deg.C for 1-10hr to afford the objective substance. The phosgene is used in a molar amount of >=1.0 times based on the 9-fluorenylmethanol and the tertiary phosphines are used in a molar amount of 0.01-1.0 based on the 9-fluorenylmethanol.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing chloroformic acid (9-fluorenylmethyl) (hereinafter abbreviated as Fmoc-CQ).

Fmoc-C1 is used as a protection reagent for amino acids, peptides, etc. That is, Fmoc-Cl is 9-fluorenylmethoxycarbonyl (hereinafter Fmo
It is abbreviated as c. ) group into the amino group of amino acids, peptides, etc.

Currently, this Fmoc group is particularly frequently used in the field of solid phase peptide synthesis.

Further, Fmoc-C° C. is not only used directly as an Fmoc-forming agent as described above, but also used in the synthesis of various active ester type Fmoc-forming agents.

Examples of active ester type Fmoc-forming agents include N-(9-fluorenylmethoxycarbonyloxy)succinimide, 9-fluorenylmethylpentafluorophenyl carbonate, and 4-(9-fluorenylmethoxycarbonyloxy) Examples include phenyldimethylsulfonium methyl sulfate. These active ester type Fmoc-forming agents, along with Fmoc-Cl, have become important reagents in peptide synthesis.

[Conventional technology and its problems]

As a method for producing Fmoc-Cl, a method in which 9-fluorenylmethanol and phosgene are reacted in dichloromethane is conventionally known (L, A, Carpino, G,
Y.

tlan, J, Org, Chem, , 37.34
04 (1972)). However, according to the inventors' research, this known method has an extremely low reaction rate, and the reaction rate is only about 80% even after 100 hours of reaction, making it impossible to obtain FmocCl in high yield. There wasn't. On the other hand, if phosgene is used in large excess, the reaction time is shortened to some extent, but in this case there are problems such as post-treatment of phosgene becomes a problem. In addition, when producing the corresponding aromatic chloroformate by reacting phenols with phosgene, 60%
A method is known in which the reaction is carried out at a temperature of °C to 180'C.

(For example, Japanese Patent Publication No. 62-61581) The object of the present invention is to efficiently produce Fmoc-Cl from 9-fluorenylmethanol and phosgene at a high reaction rate.

[Means for solving problems]

In order to solve the problems of the prior art as described above, the present inventors have conducted extensive research on the reaction between 9-fluorenylmethanol and phosgene. As a result, they discovered that surprisingly good results could be obtained by using tertiary phosphines as catalysts, and the present invention was completed.

That is, the present invention provides chloroformic acid (9-fluorenylmethanol), which is characterized by reacting 9-fluorenylmethanol and phosgene in the presence of a tertiary phosphine represented by the following general formula (I). This is a method for producing nylmethyl).

R'R''R'P (1') [In the formula, pl, R2 and R3 represent an alkyl group, an aralkyl group or an aryl group, and may be the same or independent of each other. Also, pl, Rg and R3 (both of which can form a mutually connected divalent or trivalent cyclic hydrocarbon group) The alkyl group in the tertiary phosphine used in the present invention has a carbon number of Generally 12 or more chlorhexylphosphine, tricyclohexylphosphine, dimethylphenylphosphine, ethylpentylphenylphosphine, ethylhexylphenylphosphine, dicyclohexylphenylphosphine, methyldiphenylphosphine, ethyldiphenylphosphine, isopropyldiphenylphosphine, butyldiphenylphosphine, cyclohexyl Diphenylphosphine, triphenylphosphine, benzylbutylpropylphosphine, dibenzylethylphosphine, dibenzylbutylphosphine, diphenylbenzylphosphine, dibenzylphenylphosphine, tribenzylphosphine, methylbenzylphenylphosphine, ethylbenzylphenylphosphine, propylbenzylphenylphosphine, Examples include butylbenzylphenylphosphine, ethyltetramethylenephosphine, and ethylpentamethylenephosphine.

Among these tertiary phosphines, tributylphosphine and triphenylphosphine are particularly preferable because they have a high reaction promoting effect, do not cause side reactions, and are easy to handle.

There is no problem in using a mixture of multiple types of phosphines as described above.

In the method of the present invention, phosgene is 1.0 times or more mole or more, preferably 1.0 to 2 times mole, relative to 9-fluorenylmethanol.
．． 0 times mole, particularly preferably 1.1 to 1.5 times mole, and the tertiary phosphine used varies depending on the amount of phosgene, solvent, etc., but 0.01 to 1.0 times mole, preferably 0.0 times mole. 05 to 0.2 times molar amount is used. In the present invention, the reaction is carried out in the presence of a suitable solvent, and the solvent used is an aliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, toluene or benzene, or a halogenated hydrocarbon, such as trichloroethane. or dichloromethane, or ethers. Preferred are halogenated hydrocarbons, particularly dichloromethane. Of course, in the method of the present invention, there is no problem in using a mixture of a plurality of the above-mentioned solvents. The amount of solvent varies depending on the type of solvent, but is generally 2 to 20 rnI! per gram of 9-fluorenylmethanol. ,, preferably 5 to 151I11.

In the present invention, regarding the method of mixing 9-fluorenylmethanol, phosgene, tertiary phosphines, and a solvent, for example, phosgene is dissolved in a solvent in advance, and 9-fluorenylmethanol, tertiary phosphines, and a solvent are mixed together. There is a way to add phosphine.

However, the method is not limited to this method. 9-fluorenylmethanol may be added as a solid or dissolved in a solvent.

Although the reaction temperature varies depending on the type of tertiary phosphine, it is generally maintained at -78 to 40°C, preferably 0 to 30°C, and the reaction is carried out for about 1 to 10 hours. The completion of the reaction can be determined by the disappearance of the 9-fluorenylmethanol peak in normal phase high performance liquid chromatography.

After the above reaction is completed, the target compound Fmoc-C1 can be isolated and purified by distilling off excess phosgene and the solvent, crystallizing it, and optionally recrystallizing it.

Next, the method of the present invention will be explained in more detail with reference to Examples.

Example 1 3.10 g (31.3 mmol) of phosgene was added to 30 ml of dichloromethane cooled to 0°C. Add 5.9-fluorenylmethanol to this phosgene solution. OOg
(25.5 mmol), tributylphosphine 0.51
g (2.5 mmo+) was added thereto, and the mixture was further stirred at 20°C for 4 hours. After the reaction was completed, excess phosgene and dichloromethane were distilled off to obtain an oil. Add 4mf of diethyl ether to this to crystallize it, and the desired product, chloroformic acid (9-
6.24 g of fluorenylmethyl) was obtained. (Yield 94
．． 5χ, purity 99.9χ) Melting point 63-65°CI R (C=0
) 1770cm-'' H-N M
R (CDCf 3) 64.1~4.6 (311
, m) 67.1-7.8 (8H, m) Example 2 3.20 g (32.3 mmol) of phosgene was added to 30 ml of dichloromethane cooled to 0°C. Add 5.9-fluorenylmethanol to this phosgene solution. OOg
(25.5ml1ol), triphenylphosphine 0
．． Add 65g (2.5mmol) and further heat at 20°C.
The mixture was stirred for 3 hours. After the reaction was completed, excess phosgene and dichloromethane were distilled off to obtain an oil. 4 mf of diethyl ether was added to this to crystallize it to obtain 6.10 g of chloroformic acid (9-fluorenylmethyl), the target product. (Yield: 92.5x, Purity: 99.9x) Example 3 10.0 g (101 mmol) of phosgene was added to 30 ml of dichloromethane cooled to 0'C. Add 5.9-fluorenylmethanol to this phosgene solution. OOg (
25,5mmo+) triphenylphosphine 0.065
g (0.25 mmo+) and further heat at 20°C for 2
Stir for hours. After the reaction was completed, excess phosgene and dichloromethane were distilled off to obtain an oil. 4 ml of diethyl ether was added to this to crystallize it, and the desired product, chloroformic acid (9
-fluorenylmethyl) 6.37 g were obtained. (Yield 9
6.5χ, purity 99.9χ) Comparative Example 1 4.00 g (40.4 mmol) of phosgene was added to 30 ml of dichloromethane cooled to 0'C. Add 5.9-fluorenylmethanol to this phosgene solution. OOg(2
5,4nuwol) was added as a solid, and the mixture was further stirred at 0°C for 100 hours (the reaction rate was 80X when the reaction solution was analyzed by high performance liquid chromatography).

Excess phosgene and dichloromethane were distilled off to obtain an oil. When 4 mf of diethyl ether was added to this for crystallization, 5.72 g of chloroformic acid (9-fluorenylmethyl) mixed with 9-fluorenylmethanol was obtained. (Purity 77.3χ) Comparative Example 2 15.0 g (152 mmol) of phosgene was added to 30 ml of dichloromethane cooled to 0"C. To this phosgene solution, 5.00 g (25 mmol) of 9-fluorenylmethanol was added.
, 5 mmol) was added as a solid, and further heated at 20°C.
Stir for hours. After the reaction was completed, excess phosgene and dichloromethane were distilled off to obtain an oil. 4 ml of diethyl ether was added to this for crystallization to obtain 5.70 g of chloroformic acid (9-fluorenylmethyl). (Yield 86.3χ
.

Purity 99.9χ) [Effects of the Invention] According to the present invention, chloroformic acid (
9-fluorenylmethyl) with almost quantitative yield, and is an industrially useful method.

Patent applicant: Mitsubishi Gas Chemical Co., Ltd.

Claims (1)

[Claims] Chloroformic acid (9-fluorenyl methanol) and phosgene are reacted in the presence of a tertiary phosphine represented by the following general formula (I). method for producing nylmethyl). R^1R^2R^3P(I) [In the formula, R^1, R^2 and R^3 represent an alkyl group, an aralkyl group or an aryl group, and may be the same or independent of each other. Furthermore, at least two of R^1, R^2 and R^3 can form a divalent or trivalent cyclic hydrocarbon group connected to each other. ]