JPS6136261A - Novel carbonic acid ester compound and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A carbonic acid ester compound expressed by formula I (R is alkyl or aralkyl which may be substituted by alkoxy). EXAMPLE:N-Benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide. USE:Useful as a reagent for introducing urethane type amino protecting groups, capable of introducing the amino protecting groups at ordinary temperature in a short time without requiring special heating nor cooling, and obtained as a pure compound without side reaction. PREPARATION:A haloformic acid ester expressed by formula II (X is halogen) is reacted with an N-hydroxy-5-norbornene-2,3-dicarboximide expressed by formula III in a solvent, e.g. benzene, preferably in the presence of a base, e.g. sodium hydroxide, at -80-+80 deg.C, preferably -40-+40 deg.C to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel carbonate ester compound and a method for producing the same.

The novel carbonate ester compound of the present invention is represented by the general formula (1) (wherein R means an alkyl group, an aralkyl group, or an aralkyl group substituted with an alkoxy group).

Examples of the novel carbonate ester compounds of the present invention include the following.

(1) N-tertiary butyloxycarbonyloxy-5-
norbornene-2,3-dicarboximide (2)N-
Benzyloxycarbonyloxy-5-norbornene-
2,3-dicarboximide (3) N-anisyloxycarbonyloxy-5-norbornene-2,3-dicarboximide The novel carbonate compound according to the present invention has the following general formula (TI) R-0-COX ( n) 13= (wherein, R is an alkyl group, an aralkyl group, or an aralkyl group substituted with an alkoxy group, and X is a halogen, respectively) and haloformic acid esters represented by the formula (Iff) It is produced by reacting with N-hydroxy-5-norbornene-2,3-dicarboximide. Haloformic acid esters are represented by the general formula (II), and more specifically, halogens such as chloro, fluoro, and bromine are
The R-0-Co group is an alkyloxycarbonyl group such as methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, tertiary butyloxycarbonyl, benzyloxy It means an aralkyloxycarbonyl group such as benzyl or phenethyl substituted with an alkoxy group such as carbonyl, phenethyloxycarbonyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tertiary butoxy.

The reaction of the present invention is usually carried out in a solvent, and examples of the solvent include benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, ace1-21-lyl,
Organic solvents such as ethyl acetate, butyl acetate, n-hexane, petroleum ether, etc. are used, but are not limited to these, and any general organic solvent that does not adversely affect this reaction can be used. Moreover, this reaction is preferably carried out in the presence of a base. The bases used here include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, Inorganic bases such as alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and trimethylamine, triethylamine, tripropylamine, tributylamine, dimethylethylamine, etc. aliphatic tertiary amines, dimethylaniline, diethylaniline, pyridine, pyrimidine, pyridazine, pyrazine,
Examples include organic bases such as aromatic or heterocyclic tertiary amines such as quinoline, isoquinoline, lutidine, picoline, and collidine, and these bases can also be used in combination.゛In the reaction of the present invention, the reaction temperature is not particularly limited, but it is usually carried out at -80 to 80 °C, preferably =40 to 4
Performed at 0°C.

The carbonate ester compound of the present invention is a new substance, which is used as a reagent for introducing a urethane-type amino protecting group, and is an industrially useful substance.

With the development of organic chemistry, it has become possible to synthesize complex compounds that contain two or more functional groups with different properties in the same molecule, and typical examples include the synthesis of nucleic acids and peptides. . In the chemical industry as well, it has become common to proceed with synthesis by temporarily protecting functional groups that are undesirable for the synthesis reaction, and then removing the protecting groups as necessary. For these purposes, commercialization of protective group introduction reagents for temporarily protecting functional groups has been requested.
Among these, reagents for introducing amino-protecting groups or imino-protecting groups (hereinafter referred to simply as amino-protecting groups) have established a certain market. Various types of amino protecting groups have been developed, but the most commonly used are urethane-type amino protecting groups, which are easy to remove under mild conditions and release alcohol and carbon dioxide gas during deprotection. ing. The reaction of introducing this urethane-type amino protecting group into an amino group or an imino group (hereinafter, this amino group or imino group is simply referred to as an amino group) can be explained in detail, for example, by introducing an alkyloxycarbonyl group into an amino group. This reaction differs from the reaction in which an amino acid or a peptide carboxylic acid is condensed with an amino group to obtain a stable amide bond.

Therefore, even if one type of condensation reaction between a carboxylic acid and an amino group is directly applied to the reaction for introducing a urethane-type amino protecting group, the reaction rate will of course be different, and good results cannot be expected. For example, the peptide bond-forming reaction via carbonyl atide of an amino acid or peptide with a protected N-terminal amino group was developed in 1902, and is still widely used to this day.
1957, Carpino [LA, Carpino, Journal of the American Chemical Society (J, Am
, Chem, Soc, ) 79°98 (1957)
] announced that the introduction reaction of a tertiary butyloxycarbonyl group could be carried out using tertiary butyloxycarbonyl acetate, but in this case, an expensive PH stat device had to be used, and there were other problems as described below. Due to these reasons, it has disappeared from the market. As described above, special technology is required to develop a reagent for introducing a urethane-type amino protecting group. Below, I would like to point out a problem with the reagents for introducing urethane-type amino protecting groups. Conventionally, chlorine-8-lights such as benzyloxycarbonyl chloride and tertiary-butyloxycarbonyl chloride have been known, but these are unstable. During storage, carbon dioxide and hydrochloric acid gases are gradually released, which may cause the sealed storage container to burst.If the container is open, the hydrochloric acid gas will contaminate and corrode the surrounding area, so protective measures must be taken. There were some inconveniences, such as not having to do so. In order to eliminate these inconveniences, in recent years, more stable compounds such as tertiary butyloxycarbonyl P-nitrophenyl ester and tertiary butyloxycarbonyl P-nitrophenyl ester,
Compounds such as tertiary butyloxycarbonyl-4,6-dimethylpyrimidin-2-ylthiol ester have been proposed, but tertiary butyloxycarbonyl P-nitrophenyl Esters require a long time to use because of their low reactivity, and tertiary-butyloxycarbonyl-4,6-dimethylpyrimidine-2 was removed from the market due to reports of explosion damage. The -ylthiol ester has drawbacks such as the need to carry out an extra step of decolorizing the coloring derived from sulfur after the reaction.

In order to overcome these drawbacks, the inventors of the present invention conducted research on various types of =9, and as a result, they came to invent a novel carbonate ester compound that can be used as a reagent for introducing a urethane-type amino protecting group. Moreover, the compounds of the present invention do not require special heating or cooling, and can be introduced with amino protecting groups in a short time at room temperature, and there is little risk of side reactions occurring.

The carbonate ester compound (1) according to the present invention is a stable compound, can be easily obtained as a pure compound by the method of the present invention, is not dangerous like other introduction reagents such as amide compounds, and is easy to handle. It has some excellent characteristics.

Next, the present invention will be explained by examples.

Example I N-tert-butyloxycarbonyloxy-5-norbornene-2,3-dicarboximide N-hydroxyl was added to 220 ml of tetrahydrofuran solution containing 19.39 g of tertiary-butyloxycarbonyl chloride under cooling with ice water. 180 ml of a tetrahydrofuran solution containing 25.36 g of 5-norbornene-2,3-dicarboximide and 19.81 ml of triethylamine was added dropwise over 30 minutes. After the addition, the mixture was stirred at room temperature for 2 hours and then incubated overnight. After adding 100-proof cold saturated saline solution to the reaction solution,
Extract with 400 ml of ethyl acetate.

After washing 5 times with 100 ml of saturated brine, drying over anhydrous sodium sulfate and drying under reduced pressure gives crude crystals. This was recrystallized from ethyl acetate to obtain 36.57 g of colorless needle crystals.

Melting point: 144-146°C Elemental analysis: C14H□7NO6 Calculated value: C60,20,I! 6.14. N5.
02 actual measurement value: C60, 41, H5, 98, N 5.2
1 Example 2 N-hydroxycarbonyloxy-5-norbornene-2,3-dicarboximide N-hydroxy-5-norbornene-2,3-dicarboximide was added to a solution of tetrahydrofuran 50I111 containing 17.06 g of benzyloxycarbonyl chloride under cooling with ice water. 17.92 g of 2,3-dicarboximide and 14 g of triethylamine
200 ml of tetrahydrofuran solution containing 2
It takes 0 minutes to drip. After stirring the reaction solution at room temperature for 2 hours, 100 ml of cold water was added and extracted with 360 ml of ethyl acetate. After washing with 100 ml of saturated saline five times, drying with anhydrous magnesium sulfate and evaporating to dryness, crude crystals are obtained. When this is recrystallized from ethyl acetate, colorless needle crystals 3 are obtained.
Obtain 0.13 g.

Melting point: 125-126℃ Elemental analysis: C1, I+1. , No.

Calculated value, C65,17, H4,83, N 4.47 Actual value: C64,88, H4,69, N 4.52 Example 3 N-anisyloxycarbonyloxy-5-norbornene-2,3-di A solution of tetrahydrofuran 70 containing 31.10 g of carboxyimidoanisyloxytriponyl chloride was added with N under cooling with ice water.
-Hydroxy-5-norbornene-2,3-dicarboximide 27.77g and triethylamine 21,7
250 ml of a tetrahydrofuran solution containing jnl was added dropwise over a period of 1 hour. After stirring this reaction solution at room temperature for 2 hours, 100 ml of cold water was added, and 300 ml of ethyl acetate was added.
Extract with l. After washing 5 times with 100ml of saturated saline,
Dry over anhydrous sodium sulfate and evaporate to dryness to obtain crude crystals. This was recrystallized from ethyl acetate to obtain 48.93 g of a colorless prism product.

Melting point: 111-112℃ (decomposition) Elemental analysis: C1, H, □No.

Claims (1)

[Claims] 1. A novel carbonate ester represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R means an aralkyl group substituted with an alkyl group, an aralkyl group, or an alkoxy group) Compound. The compound according to claim 1, which is 2,N-tert-butyloxycarbonyloxy-5-norbornene-2,3-dicarboximide. The compound according to claim 1, which is 3,N-benzyloxycarbonyloxy-5-norbornene-2,3-dicarboximide. The compound according to claim 1, which is 4,N-anisyloxycarbonyloxy-5-norbornene-2,3-dicarboximide. 5. The haloformic acid esters represented by the general formula R-O-COX (wherein R is an alkyl group, an aralkyl group, or an aralkyl group substituted with an alkoxy group, and X means a halogen) are combined with the formula ▲mathematical formula , chemical formula, table, etc. ▼ N-hydroxy-5-norbornene-2,
Claims characterized in that a novel carbonate ester compound represented by the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (in the formula, R has the same meaning as before) is obtained by the action of 3-dicarboximide. A method for producing the compound according to item 1.