JPH03170440A - Method for protecting and deprotecting carboxylic acid, phosphoric acid or sulfonic acid - Google Patents

Abstract

PURPOSE:To protect and deprotect a carboxylic acid, phosphoric acid or sulfonic acid group under a neutral condition without damaging other functional groups by protecting the carboxylic acid, phosphoric acid or sulfonic acid group with a m-methoxybenzyl group or a derivative thereof and subsequently irradiating the protected group with light. CONSTITUTION:The alcohol derivative of a protecting group (e.g. m- methoxybenzyl alcohol) is made to react with the acid chloride of a compound to be protected (e.g. benzoyl chloride) in order to protect a carboxylic acid, phosphoric acid or sulfonic acid group with the m-methoxybenzyl group. As another method, the alkali metal salt of the compound to be protected (e.g. potassium benzoate) may be reacted with the halogenated benzyl derivative of the protecting group. The deprotecting reaction is performed, e.g. by irradiating the protected product with a low pressure, high pressure or superhigh pressure mercury lamp or xenon lamp of 5-450W, etc., as a light source in a solvent such as water-containing acetone in a concentration of the reaction substrate of 0.5-50mM for 10mim to 10 hours.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a method for protecting and deprotecting carboxylic acid, phosphoric acid, or sulfonic acid, which is useful in manufacturing processes of various organic compounds and photochemical processes. It is something.

(Prior Art) There is a vast amount of knowledge regarding the protection and deprotection of functional groups of organic compounds, and J. F. W. McComey (J.F.W.
Mcomte) &W Protective Groups
In Organic Chemistry (Protect)
ve Groupsin Organic CheII
listry) Plenum Press, T. one. green(
Protective Graves in Organic Synthesis (T.W. Green)
ive Groups in Organic Syn
(thesis) Many methods for protecting carboxylic acids, phosphoric acids, and sulfonic acids are described in books such as those published by Wiley Interscience Publishing. Generally, to remove these protecting groups (esters), a hydrolysis method using hydroxyl ions or hydrogen ions is used. However, when there are two or more ester sites in a molecule, only one of them is selectively cleaved, or when compounds or functional groups that are damaged by acid/alkali hydrolysis coexist, conventional Hydrolysis methods using acids and alkalis are often not applicable. Therefore, several improved methods have been developed.

under mild conditions (neutral conditions) without damaging other functional groups.
One way to cleave the ester moiety is to use a photosensitive protecting group. The advantage of deprotecting photosensitive protecting groups with light is that light is harmless and easy to handle as an energy source, and there are many reports of protecting groups that can be removed with light, including synthetic, organic, chemical, and photoprotective groups. Chemistry (Synthetic Organic Ch.
emistry), pp. 357-423, Plenum Press, Israel Journal Chemistry-Volume 12,
1974, p. 103, Synthesis, 1980, p. 1, etc. As photosensitive protecting groups used for carboxylic acid or phosphoric acid, O-nitrobenzyl group, O-nitrophenylaξno group, p-methoxyphenacyl group, etc. are known. In the case of the 0-nitrobenzyl group, which is often used as a protecting group that can be removed with light, although the 0-nitrobenzyl group is fast, it leaves 0-nitrosobenzaldehyde in the system. If the deprotected compound has an amino group, it has the disadvantage that it reacts to form a Schiff base. 0
Although the -nitrophenylamino group has excellent responsiveness, its introduction into compounds is a problem. Furthermore, the p-methoxyphenacyl group is eliminated faster than the 0-nitrobenzyl group, but
There are problems with irradiation with short wavelength light and the risk of decarboxylation during deprotection. As described above, conventional photodeprotection methods have various drawbacks, and there are limits to their general use in organic synthesis.

(Problems to be Solved by the Invention) Therefore, the purpose of the present invention is to provide a method for protecting and deprotecting carboxylic acids, phosphoric acids, and sulfonic acids under neutral conditions without damaging other functional groups. be.

(Means for Solving the Problems) The above objects of the present invention are as follows: (1) As a protecting group for carboxylic acid, phosphoric acid or sulfonic acid to be protected in a compound having carboxylic acid, phosphoric acid or sulfonic acid, A method for protecting carboxylic acid, phosphoric acid or sulfonic acid characterized by using m-methoxybenzyl group or its derivative, and (2) carboxylic acid, phosphoric acid or sulfonic acid protected with m-methoxybenzyl group or its derivative This was accomplished by a method for deprotecting carboxylic acids, phosphoric acids, or sulfonic acids, which is characterized by irradiating light onto compounds having the following properties.

The group used as a protecting group in the present invention is an m-methoxybenzyl group or a group having a substituent on its benzene nucleus. Here, examples of the substituent include an alkoxy group, a halogen atom, an alkoxycarbonyl group, an alkylcarbamoyl group, and the like. The number of carbon atoms in the alkoxy group, alkoxycarbonyl group, and alkyl group is preferably 1 to 17, and the alkyl portion of each substituent may be linear, branched, or cyclic, and other substituents may be present. Good too.

There is no particular limitation on the compounds having carboxylic acid, phosphoric acid or sulfonic acid that are protected by the protecting group of the present invention, and the protecting group of the present invention can protect the carboxylic acid, phosphoric acid or sulfonic acid of various compounds. Can be done. Examples of compounds protected with the protecting groups of the present invention are shown below. PS 1 0 PS-2 0 PS 3 0 PS 4 n PS-5 0 PS 6 0 C-nin PS 7 0 PS 8 0 PS 9 0 IR ν (C=0) 1 735cm MASS M1 325 PS 10 0 PS 11 PS l2 In order to protect the carboxylic acid, phosphoric acid, or sulfonic acid of a compound having a carboxylic acid, phosphoric acid, or sulfonic acid with the protecting group of the present invention, the alcohol form of the protecting group of the present invention (for example, m-
Methoxybenzyl alcohol) may be reacted with the acid chloride of the compound to be protected (eg, benzoyl chloride).

In addition, as another method, an alkali metal salt of the protected compound (
For example, there is a method of reacting potassium benzoate) with a halogenated benzyl compound of the protecting group of the present invention (for example, m-methoxyhenzyl chloride).

Next, a method for deprotecting the m-methoxybenzyl group or its derivatives by light irradiation will be explained. Selection of reaction conditions is very important for efficient deprotection by light irradiation. The light source, solvent, concentration, and reaction time will be explained in this order. Preferred types of light sources include low-pressure mercury lamps, high-pressure mercury lamps, ultra-high-pressure mercury lamps, xenon lamps, and mercury-xenon lamps. The output of the light source is 1 to 1 kW,
Preferably it is 5-450W. Preferred solvents include aqueous acetonetrile, aqueous tetrahydrofuran, and aqueous dioxane. The concentration of the reaction substrate is 0. 1~
A range of 300mM is good, preferably 0.5-50mM
is within the range of The reaction time is preferably 10 minutes to 10 minutes.
It is a range of time. When there are two or more ester sites in the molecule of an organic compound, one of them is selectively cleaved, or when there is a functional group in the molecule that can be damaged by acid or alkali hydrolysis, this According to the invention, if m-methoxybenzyl derivatives are introduced into a compound as a Wt-retaining group for carboxylic acid, phosphoric acid, or sulfonic acid, deprotection of the introduced ester moiety can be achieved under neutral conditions by irradiation with light. Therefore, the protection and deprotection methods of the present invention are useful for the synthesis of various compounds.

Example 1 Protection of carboxylic acid of benzoic acid (in the case of PS-1)> 1.38 g (0.01 mol) of m-methoxybenzyl alcohol and 1.3 g (0.01 mol) of m-methoxybenzyl alcohol and 1. Olg (0.01 mol) and added 1.0 mol of benzoyl chloride to the solution. 22 g (0.01 mol) was added and stirred at room temperature for 3 hours.

After distilling off the solvent under reduced pressure, 200% of methylene chloride was added,
Wash twice with 200 d of water. After drying the organic layer over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate-4:l) to give 2.20 g of an oil (yield: 91
%) was obtained.

I R v C=0 1720CI1-''HN
Old (COC f 3) 63.67 (S.311.O
CH. ), 5.38 (S.2H.CHzO), 6.82
-8.15 (m.9H, φ) MASS M” 24
2 Phosphoric acid and sulfonic acid can be combined in the same manner.

Example 2 <Deprotection> 2 of various compounds protected with m-methoxybenzyl group etc.
mM acetonitrile/phosphate buffer (pH 7.0)
) (1:1) solution is put into a quartz cell, and from there 5
A 5W low-pressure mercury lamp was placed at a distance of cm and irradiated. The reduction rate constant K of the starting compound was determined by high performance liquid chromatography, 0.0. is the absorbance at 245n+m, and the relative reaction efficiency is K/(1-10°1・)
The efficiency of deprotection was evaluated. The results are shown in Table 1. (Comparative Example) A solution of 2 mM of O-nitrobenzyl benzoate in acetonitrile/phosphate buffer (pH 7.0) (1:1) was used to measure the reduction rate constant K of O-nitrobenzyl benzoate in the same manner as in the example.

The results are shown in Table 1. The m-methoxybenzyl group and its derivatives have higher reaction efficiency and can be deprotected more quickly than the 0-nitrobenzyl group, which is often used as a photosensitive protecting group.

Example 3 tert-butoxyluponylserine-m-methoxyhenzyl ester 1. 5g (4.6mmol)
Wotetrahydrofuran/phosphate buffer (pH 7.0)
) (5:l) room was placed in an internal irradiation type photoreaction container, and irradiated for 3 hours with a 450 W high-pressure mercury lamp placed in a quartz jacket at room temperature under a nitrogen atmosphere.

The solvent was distilled off under reduced pressure, purified by silichromatography (chloroform/methanol 75:25), and tert
-Butoxycarbonylserine 0.76g (yield 75%)
I got it.

(Effects of the Invention) According to the present invention, carboxylic acid, phosphoric acid, and sulfonic acid can be protected and deprotected under neutral conditions without damaging other functional groups.

Claims (2)

[Claims] (1) A carboxylic acid characterized by using an m-methoxybenzyl group or a derivative thereof as a protecting group for the carboxylic acid, phosphoric acid, or sulfonic acid to be protected in a compound having a carboxylic acid, phosphoric acid, or sulfonic acid. , phosphoric or sulfonic acid protection methods. (2) A method for deprotecting carboxylic acid, phosphoric acid, or sulfonic acid, which comprises irradiating a compound having carboxylic acid, phosphoric acid, or sulfonic acid protected with an m-methoxybenzyl group or a derivative thereof.