CH637909A5 - Removal of carboxyl-protecting groups - Google Patents

Description

The present invention relates to a process for the elimination of carboxy-protecting groups as defined in claim 1.

The above procedure can be represented by the following reaction scheme:

R'COOCH2-

(I)

R

Lewis acid

R'COOH (II)

wherein R'CO represents a carboxylic acid group, with the exception of cephalosporins and R represents hydrogen or a substituent in the phenyl group.

In organic chemistry, carboxy-protecting groups are usually used under certain conditions to prevent the cleavage of unstable groups in the molecule. Benzyl esters are representative of this type of group where catalytic hydrogenation is used to remove the protecting group. However, this process requires expensive catalysts and explosive hydrogen and is therefore poorly suited for use on a large scale. In particular, unsubstituted benzyl esters are difficult to split off from complicated molecules with the aid of catalytic hydrogenation.

It has now been found that carbobenzoxy groups and benzyl esters are easily cleaved with the aid of a Lewis acid, the corresponding acids being released. The present invention is based on this fact. As a result, it can also be said that the benzyl ester is therefore one of the most useful carboxy-protecting groups suitable for large-scale use. The same process applied to benzyl esters of cephalosporins and 1-oxa analogs thereof forms the content of JP patent application 23 602/1976. It has now been found that the method can also be applied to other compounds and that is why this additional application was made.

io Preferably R is hydrogen, alkyl, alkoxy, hydroxy, aryloxy, acyloxy, amino, alkylamino, acylamino, car-boxy, carbalkoxy, carbamoyl or halogen, each with up to 12 carbon atoms. In particular, R is hydrogen, Ci-Cs-alkoxy or alkylhydroxy, Cs-Cio-aryloxy, Ci-Ci2-Acy-ls loxy, amino, Ci-Cs-alkylamino, Ci-Cs-acylamino, car-boxy, C2-C6 -Carbalkoxy, carbamoyl or halogen, and the most preferred meanings of R are chlorobenzyl, bromobenzyl, Ci-C3-alkoxybenzyl, Ci-C3-alkyl-benzyl, (including, for example, dimethylbenzyl, trimethylbenzyl) 20 and unsubstituted benzyl esters.

In the process according to the invention, the reaction is preferably carried out at a temperature of −10 to 100 ° C., in particular 0-40 ° C.

As the Lewis acids can be used: Bortrihalo-25 halides (such as boron trichloride, boron tribromide, boron trifluoride), titanium tetrahalides (such as titanium tetrachloride, titanium tetra bromide), Zirkoniumtetrahalogenide (for example, zirconium tetrachloride, tin tetrabromide), antimony (as antimony trichloride, antimony pentachloride), bismuth trichloride , Alu-30 minium trihalides (e.g. aluminum trichloride, aluminum umtribromide), zinc halides (e.g. zinc chloride, zinc bromide), iron (III) halides (e.g. iron (III) chloride, iron (III) bromide), zinc sulfate , Trifluoroacetic acid and toluene-p-sulfonic acid.

35 The solvents used are preferably conventional aprotic solvents such as hydrocarbons (e.g. pentane, hexane, petroleum ether, benzene, toluene, xylene), halogenated hydrocarbons (e.g. methylene chloride, chloroform, dichloroethane, trichloroethane, chlorobenzene), 40 carbon disulfide, nitrocarbons (nitromethane, nitrobenzene, nitrobenzene ) or ether (e.g. diethyl ether, methyl isobutyl ether, tetrahydrofuran, tetrahydropyran, dioxane, diphenyl ether, anisole) or mixtures of these solvents.

45 The least side reactions are observed when using nitroalkanes, carbon disulfide, halogenated hydrocarbons or ether or mixtures of the solvents mentioned.

Methylene chloride, anisole or a mixture of methylene chloride and nitromethane or anisole is one of the most preferred solvents.

The reaction is accelerated and proceeds smoother in the presence of a carbonium cation acceptor in the reaction medium. Examples of this are fertilize nucleophilic Verbin-55, e.g. Anisole, phenol, nitrophenol, thiophene, etc.

The most preferred reaction conditions are such that 1.5-10 molar equivalents of a Lewis acid (especially aluminum chloride), 1.5-10 molar equivalents of a carbonium cation acceptor (especially 60 anisole) and 1 molar equivalent of the benzyl ester (I) in one Mixture of nitroalkane (in particular nitromethane) or ayloxyalkane (in particular anisole) or haloalkane (in particular methylene chloride) (5: 1 to 1:10, in particular 1: 1-1: 4) at room temperature for 2-7 hours.

The reaction rate is largely dependent on the concentration of the benzyl ester, the Lewis acid and the cation acceptor, on temperature and

Solvent, but it takes place under favorable conditions within 1-24 h. At room temperature in the presence of a cation acceptor, the reaction is usually complete after 1-12 h.

If the reaction product is in the form of a salt or an organometallic ester derivative, it can be mixed with an acid (for example mineral acids, carboxylic acids, sulfonic acids, acidic ion exchange resins) or a base (for example alkali metal hydroxides, alkali metal carbonates, basic ion exchange resins), preferably in the presence of water be hydrolyzed. If a cation acceptor is used, the product is in the form of a salt. If the cation acceptor mentioned is not used, the product can be in the form of an organometallic ester. Both of these products can be hydrolyzed in a conventional manner with an aqueous mineral acid (e.g. hydrochloric acid, sulfuric acid, nitric acid).

The free acids obtained can be isolated from the reaction mixture, the solvent, unreacted starting materials and other by-products in a conventional manner, e.g. by changing the pH, extraction, recrystallization, absorption, concentration and precipitation and can be purified by recrystallization, re-precipitation, chromatography, washing and drying.

A particular problem with the present invention is to separate the spent Lewis acid from the reaction mixture. Typically, the Lewis acid or its derivative is soluble in water with decomposition to form a precipitate, an emulsion or a sol. In such cases, acids can be added to the reaction mixture to dissolve the solids or a highly porous polymer can be used to absorb the high molecular weight free acids.

The process described can also be used to split off some groups under the same conditions (e.g. t-butoxycarbonyl or carbobenzoxy) if they are present together with benzyl groups in the molecule. These cases are also intended to be encompassed by the present invention.

Examples

The following examples are intended to explain the process according to the invention in more detail, but without restricting it in any way.

example 1

To a solution of 1 g of N-t-butoxycarbonyl-L-phenyl-alanine-benzyl ester in 10 ml of methylene chloride was added 1 g of aluminum chloride in 12 ml of anisole, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into an aqueous

637909

Poured sodium bicarbonate solution and filtered to remove insoluble solids. The filtrate was washed with methylene chloride, acidified to pH 2.5 by adding hydrochloric acid, and absorbed on highly porous polymer HP-20 (Mitsubishi Chemical Co., Ltd.). After washing with water, the resin was eluted with methanol. After concentration of the eluate, 0.3 g of crystals of L-phenylalanine with a melting point of 270 ° C. were obtained. Yield: 54%.

Example 2

A solution of 4 g of aluminum chloride in 50 ml of nitromethane and 3 ml of anisole was added to a solution of 3 g of benzyl-2-p-isobutylphenylpropionate in 18 ml of methylene chloride at 0 ° C. and the mixture was stirred at room temperature for 6 hours. The reaction mixture was then diluted with ethyl acetate, washed with hydrochloric acid and water, dried and concentrated. The residue was recrystallized from n-hexane to give 186 mg of 2-p-isobutylphenyl-propionic acid, mp. 75-77.5 ° C. Yield: 91%.

Example 3

A mixture of 15 mg of 3-phenylacetamido-1 - (a-carbo-benzoxy-p-hydroxybenzyl) -azetidin-2-one, 0.5 ml of methylene chloride, 12 mg of aluminum chloride and 0.2 ml of anisole was added for 8 hours at - Kept at 20 ° C. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, dried and concentrated in vacuo. By recrystallizing the residue from a mixture of ethyl acetate and ether, 9 mg of 3-phenylacetamido-1 - (a-carboxy-p-hydroxybenzyl) -azetidin-2-one of mp 134-141 ° C. were obtained. Yield: 75%.

Example 4

A mixture of 218 mg of benzylphenylacetate, 2 ml of methylene chloride, 357 mg of aluminum chloride and 1 ml of nitromethane was stirred for 1 hour while cooling with ice. The mixture was acidified by adding cold dilute hydrochloric acid and extracted with methylene chloride. The organic phase was extracted again with a 5% aqueous sodium hydrogen carbonate solution. The aqueous extract was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to give 114 mg of phenylacetic acid, mp. 77 ° C. Yield: 87%.

Example 5

In the analogous procedure as in Example 4, 200 mg of p-methoxy-benzylphenylacetate were hydrolyzed with aluminum chloride in methylene chloride and anisole for 5 hours, phenylacetic acid being obtained in an 8% yield.

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Claims (10)

637909 PATENT CLAIMS 1. A process for cleaving a carboxy-protecting group to form the corresponding carboxylic acid, characterized in that a benzyl ester of a carboxylic acid in which the phenyl group of the benzyl radical is optionally simply substituted, with the exception of those esters of cephalosporins and 1-oxa analogues thereof a Lewis acid is treated if necessary followed by hydrolysis. 2. The method of claim 1, wherein the reaction is carried out in a solvent. 3. The method of claim 1, wherein the Lewis acid is aluminum chloride, titanium tetrachloride, tin tetrachloride, boron trifluoride or zinc chloride. 4. The method according to claim 1, wherein the benzyl ester is a chlorobenzyl ester, bromobenzyl ester, Ci-C3-alkoxy-benzyl ester, Ci-C3-alkyl benzyl ester or an unsubstituted benzyl ester. 5. The method according to claim 2, wherein the reaction is carried out in one of the solvents nitroalkane, carbon disulfide, halogenated hydrocarbon or an ether or in a mixture of said solvents. 6. The method according to claim 2, wherein the reaction is carried out in methylene chloride or in a mixture of methylene chloride or anisole with nitromethane. 7. The method of claim 1, wherein the reaction is carried out in the presence of a carbonium ion acceptor. 8. The method of claim 1, wherein the reaction is carried out in the presence of anisole. 9. The method of claim 1, wherein the reaction is carried out at a temperature of 0-40 ° C. 10. The method of claim 1, wherein the hydrolysis is carried out with an aqueous mineral acid.