JPS6344138B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel and useful method for producing N-substituted aretins or N-substituted aretheins, which are important compounds as pharmaceuticals or synthetic intermediates thereof. Many methods have been known for producing N-substituted aretin or N-substituted arethein, but among them, the simplest method is to condense N-substituted-β-alanine and cystamine or cysteamine using a condensation reagent. It is a manufacturing method that is said to be industrially advantageous. Condensation reagents used in these reactions include:
Carbodiimides (Japanese Patent Publication No. 41-2896), carbodiimidazole (Japanese Patent Publication No. 44-3324), sulfonyl chlorides (Japanese Patent Publication No. 47-26490), dimethylformamide chloride (Japanese Patent Publication No. 47-49572)
), tertiary phosphines or phosphites (Japanese Patent Publication No. 51-32607), diphenylphosphoric azide or diethyl phosphoric cyanide (Japanese Patent Publication No. 53-25521), pyridinium salts (Japanese Patent Publication No. 54-9222), etc. It is being However, when using these condensation reagents, there are concerns that the reaction reagents are expensive, unstable and difficult to handle, or that the reaction operations are complicated, or that they are unsafe to handle. From an industrial perspective, there are problems with chemical properties, defects in the reagent itself, resulting in low reaction yields, many side reactions, making it impossible to obtain high-purity products, and complicated process operations. There are many problems and it is not always satisfactory. Therefore, the present inventors investigated various condensation reagents of N-substituted-β-alanine and cystamine or cysteamine, and found that the general formula (1) or (2)

【formula】

[Formula] (wherein, R ¹ is O- or P-nitrophenyl, P
- Substituted phenyl group such as cyanophenyl, X is a hydrogen atom or a halogen atom such as chlorine or bromine,
R ² represents a lower alkyl group such as methyl or ethyl, or an aryl group such as phenyl or P-halogen-substituted phenyl. ) by directly reacting N-substituted-β-alanine with cystamine or cysteamine in the presence of phenylphosphonic acid esters or sulfonyl acid esters,
The present invention was completed by discovering that N-substituted aretin or N-substituted arethein can be produced with high purity and high yield. N of the raw material compound and target compound in the present invention
-Substitution means substitution with a pantoyl group, a lower acyl group generally used as a protecting group for an amino group, an alkoxycarbonyl group, a tosyl group, a phthalyl group, etc. The raw material compounds used in this reaction include N-substituted-β-alanine in its free form, as well as organic amine salts such as triethylamine salts and trimethylamine salts, alkali metal salts such as sodium and potassium salts, and alkaline earth salts such as calcium salts. Metal salts are used. Cystamine or cysteamine, one of the raw materials, is used in its free form, as well as mineral acid salts such as carbonate, hydrochloride, and sulfate. In addition, in this reaction, as sulfonic acid is produced as a by-product as the reaction progresses, free N-substituted-β-
In the case of alanine, bases with a deoxidizing effect, such as tertiary amines such as triethylamine and tributylamine, heterocyclic bases such as pyridine and methylmorpholine, and inorganic salts such as sodium carbonate and sodium heavy carbon, are used. When carboxylates of these bases are used as starting compounds, there is no need to newly use these bases. To carry out the present invention, one equivalent of N-substituted-β-alanine or a salt thereof and, if necessary, an excess amount of base are dissolved or suspended in an organic solvent, and phenylphosphonic acid esters or sulfonic acid esters 1 to
Add 1.5 equivalents and add 0.5 or 1 equivalent of cystamine or cysteamine or a salt thereof under stirring.
Just add an equivalent amount and react. The solvent used in the reaction is not particularly limited as long as it does not participate in this reaction, and dimethylformamide, dimethylacetamide, pyridine, dichloroethane, acetone, dioxane, etc. are usually used. Although the reaction temperature can be -20°C to 100°C, it is generally carried out at 0°C to 30°C, and the reaction is completed in several hours. In the method of the present invention, the reaction proceeds selectively under the above-mentioned mild reaction conditions, and even when the N-substituent contains a hydroxyl group such as a pantoyl group, there is no side reaction. It can be obtained with high purity and high yield. Furthermore, since the reaction reagent is also a stable crystalline solid, the process operation is simple and the method is extremely advantageous from an industrial perspective. Examples will be described below. Example 1 2.34 g of N-formyl-β-alanine and 2.02 g of triethylamine are dissolved in 40 ml of pyridine, and 6.88 g of 6-chloro-1-P-chlorobenzenesulfonyloxybenzotriazole is added while stirring under ice cooling. Next, 1.52 g of cystamine is added and reacted at room temperature for 2 hours. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of water, extracted twice with 50 ml of chloroform, and the aqueous layer was mixed with 25 ml of ion exchange resin SK-IB and SA.
-20A 25 ml mixed bed column, and the eluate was concentrated to dryness under reduced pressure to obtain 3.16 g of N-formylacetin (yield 90.3%). Example 2 4.77 g of calcium pantothenate and 0.404 g of triethylamine were dissolved in 60 ml of dimethylformamide, and 8.26 g of 6-chloro-1-p-chlorobenzenesulfonyloxybenzotriazole was dissolved in 60 ml of dimethylformamide.
Add g. Next, 1.52 g of cystamine is added and reacted at room temperature for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was dissolved in 150 ml of water, and 75 ml of chloroform was added.
After extraction twice with ml, the aqueous layer was treated with ion exchange resin SK-
Treated with a mixed bed column of 30 ml of IB and 30 ml of SA-20A, the eluate was concentrated under reduced pressure, and 9.33 g of 50% pantethine aqueous solution was obtained.
(yield 84.1%). Example 3 The reaction was carried out in the same manner using 1.54 g of cysteamine instead of cystamine in Example 1. After extraction, the aqueous layer was mixed with 35 ml of ion exchange resin SK-IB and WA-
21 Treated with a 35 ml mixed bed column to obtain 2.62 g of N-formylarethein (yield 74.4%). Example 4 Cysteamine instead of cystamine in Example 2
Using 1.54g, the reaction and post-treatment were carried out in the same way,
After extraction, the aqueous layer was mixed with 40ml of ion exchange resin SK-IB.
It is treated with a WA-21 40 ml mixed bed column to obtain 7.80 g of a 50% pantetheine aqueous solution (yield 7.01%). Example 5 7.18 g of N-formyl-β-alanine tetrabutylammonium and 1.52 g of cystamine were added to pyridine.
Dissolve the solution in 75 ml, add 9.6 g of bis(p-nitrophenyl phenylphosphonate) and react for 4 hours while stirring at room temperature. After the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of water, extracted twice with 50 ml of chloroform, and the aqueous layer was mixed with 20 ml of ion exchange resin SK-IB and SA-
20A 20ml mixed bed column, and the eluate was concentrated under reduced pressure to obtain 3.34g of N-formylacetin (yield 95.4%). Example 6 Pantothenic acid/tetrabutylammonium 9.22
g and cystamine 1.52 g with dimethylformamide 75
ml, add 4.00 g of bis(p-nitrophenyl phenylphosphonate) under stirring at room temperature, and react for 4 hours. After the reaction, the solvent was distilled off under reduced pressure and the residue was dissolved in water.
After dissolving in 100ml and extracting twice with 50ml of chloroform,
The aqueous layer was mixed with 25ml of ion exchange resin SK-IB and SA-20A25.
ml mixed bed column, and the eluate was concentrated under reduced pressure to obtain 10.05 g of 50% pantethine aqueous solution (yield: 90.6
%). Example 7 Bis(o-nitrophenyl) phenylphosphonate is used instead of bis(p-nitrophenyl) phenylphosphonate in Example 6. Everything else was carried out in the same manner to obtain 10.28 g of a 50% pantethine aqueous solution (yield 92.7%). Example 8 Cysteamine instead of cystamine in Example 5
The reaction was carried out in the same manner using 1.54 g, and after extraction, the aqueous layer was mixed with 30 ml of ion exchange resin SK-IB and WA-
21 Treated with a 30 ml mixed bed column to obtain 2.85 g of N-formylarethein (yield 81.0%). Example 9 Cysteamine in place of cystamine in Example 6
The reaction was carried out in the same manner using 1.54 g, and after extraction, the aqueous layer was mixed with 30 ml of ion exchange resin SK-IB and WA-
21 Process in a 30 ml mixed bed column to obtain 8.84 g of 50% pantetheine aqueous solution (yield 79.5%).

Claims (1)

[Claims] 1 N-substituted aretin or N-substituted arethein characterized by reacting N-substituted-β-alanine or a salt thereof with cystamine or cysteamine or a salt thereof in the presence of phenylphosphonic acid esters or sulfonyloxybenzotriazoles. manufacturing method.