JP2558313B2 - Dehydration condensing agent and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a dehydrating condensing agent in synthetic organic chemical reactions.

More specifically, it relates to a novel dehydration condensation agent having a high dehydration condensation reaction yield.

[Conventional technology]

Conventionally, as a dehydrating condensing agent in synthetic organic chemical reaction, the formula: Dicyclohexylcarbodiimide represented by {JCSh
eehan and GHHess, J. Am. Chem. Soc., 77 , 1067 (1955);
A. Buzas, C. Egnell and P. Freon, Compt.rend ., 252 , 896
(1961); 255, 945 (1962). } (Abbreviated as DCC) or the formula: R ² OCON = NCOOR ² + P (C ₆ H ₅ ) ₃ (In the formula, R ² represents an alkyl group having 1 to 5 carbon atoms.) [O.Mitsunobu, Synthesis, 1 (1981)] and the formula: Reactants represented by a mixed system such as {T. Mukaiyama, Angew . Chem . Int .Ed., 15 , 94 (1976)} are known.

[Problems to be Solved by the Invention] The above-mentioned conventionally used dehydration-condensation agents have low reaction yields, and there is a demand for dehydration-condensation agents that allow the reaction to proceed at a quantitative yield.

In addition, dicyclohexylcarbodiimide (DCC) and dipyridyl sulfide (DDS), which are currently widely used as condensing agents for esters, amides, peptides, lactams, etc., can be treated with water addition products and water addition decomposition products after the completion of the reaction Since it cannot be easily removed to the outside of the reaction system, it is forced to use a complicated means for separating and purifying the product. In particular, DCC is used as a condensing agent during automatic peptide synthesis,
After the reaction, it is difficult to remove N, N'-dicyclohexylurea, which is a water adduct, from the reactor, and problems such as DCC mucous membrane stimulation and safety are left.

The object of the present invention is to provide a dehydration condensing agent that promotes the reaction in a yield close to a quantitative yield, and further, it is possible to easily remove water addition products and water addition decomposition products after the reaction from the reaction system. The purpose of the present invention is to provide a dehydration-condensation agent which facilitates separation and purification of products.

A further object of the present invention is to provide a dehydration condensation agent which is highly safe in terms of reaction operation safety.

[Means for solving the problem]

The present inventors have completed the present invention as a result of earnestly researching to solve the problems of the conventional condensing agents and to find a more excellent dehydrating condensing agent.

That is, the present invention is a dehydration condensation agent represented by the general formula (I).

However, in the formula (I), L is a formula: Indicates a group. [In the formula L, X ¹ and X ² are each independently a hydrogen atom,
A lower alkyl group having 1 to 5 carbon atoms or a halogen atom, a nitro group, a group of -COOR ¹ (R ¹ represents a lower alkyl group having 1 to 4 carbon atoms), or X ¹ and X ² together Nari expression: {In the formula, X ³ and X ⁴ are, independently of each other, a hydrogen atom and a carbon number of 1 to 1.
A lower alkyl group of 4, or a halogen atom, a nitro group,
R ² SO ₂ — group (R ² is a lower alkyl group having 1 to 4 carbon atoms or an aryl group). } Is represented. Another invention is a method for producing the dehydration condensing agent, which comprises a 2-oxazolone derivative represented by the general formula (II): [Wherein, in formula (II), X ¹ and X ² are each independently a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a halogen atom, a nitro atom, —COOR ¹ (R ¹ is 1 to 4 carbon atoms) Represents a lower alkyl group), or X ¹ and X ² are taken together to form the formula: {In the formula, X ³ and X ⁴ are each independently a hydrogen atom or a carbon number of 1 to 4
Lower alkyl group, halogen atom, nitro group, R ²
Represents a SO ₂ — group (R ² represents a lower alkyl group having 1 to 4 carbon atoms or an aryl group). }. ] The phosphorus oxyhalide represented by the general formula (III) (In the formula, Hal represents a halogen atom.) The general formula (I) characterized by reacting in the presence of a base. Is a method for producing a dehydration condensing agent.

However, the dehydration condensation agent of the formula (I) is the dehydration condensation agent according to claim 1. The reaction molar ratio of the 2-oxazolone derivative represented by the general formula (II) to the phosphorus oxyhalide represented by the general formula (III) is usually 0.5 to 1.0 mole of phosphorus oxyhalide, preferably 3 to 2 moles of the 2-oxazolone derivative. Is 0.8 to 1.0 mol. The base may be an alkyl metal, a metal hydride or the like, but is preferably pyridine or triethylamine.

The base is usually 1. to the 2-oxazolone derivative mainly for the purpose of neutralizing hydrogen halide formed in the reaction.
Use 0 to 5.0 times mol.

The reaction temperature is usually -70 ° C to 50 ° C, preferably 0 to 10 ° C.
Is.

 The reaction time is about 1 to 20 hours.

This reaction is carried out without solvent or in a solvent such as halogenated hydrocarbons, ethers and aromatic hydrocarbons.

Examples of halogenated hydrocarbons include methylene chloride, chloroform, carbon tetrachloride, dichloroethane and the like. Examples of ethers include diethyl ether, tetrahydrofuran, 1,4-dioxane, glyme and the like.

Examples of aromatic hydrocarbons include benzene and toluene.

In this reaction, it is preferable to use a dry solvent because the reaction examples and products used are unstable to water.

The product is usually separated and purified by a silica gel column or a recrystallization method.

The general formula (II) which is the main raw material of the novel dehydration condensation agent of the present invention
The 2-oxazolone derivative represented by is illustrated below.

For example, 2-oxazolone, 4-methyl-2-oxazolone, 5-methyl-2-oxazolone, 4,5-dimethyl-2-oxazolone, 4-ethyl-2-oxazolone,
5-ethyl-2-oxazolone, 4,5-diethyl-2-
Oxazolone, 4-propyl-2-oxazolone, 5-
Propyl-2-oxazolone, 4,5-dipropyl-2-
Oxazolone, 4-butyl-2-oxazolone, 5-butyl-2-oxazolone, 4,5-dibutyl-2-oxazolone, 4-pentyl-2-oxazolone, 5-pentyl-2-oxazolone, 4,5-dipentyl- 2-oxazolone, 4-fluoro-2-oxazolone, 5-fluoro-2-oxazolone, 4,5-difluoro-2-oxazolone, 4-chloro-2-oxazolone, 5-chloro-
2-oxazolone, 4,5-dichloro-2-oxazolone, 4-bromo-2-oxazolone, 5-bromo-2-
Oxazolone, 4,5-dibromo-2-oxazolone, 4
-Nitro-2-oxazolone, 5-nitro-2-oxazolone, 4,5-dinitro-2-oxazolone, 4-methoxycarbonyl-2-oxazolone, 5-methoxycarbonyl-2-oxazolone, 4,5-dimethoxycarbonyl- 2-oxazolone, 4-ethoxycarbonyl-2-
Examples thereof include oxazolone, 4,5-diethoxycarbonyl-2-oxazolone, 2-benzoxazolinone, and the homologues thereof can also be used.

The phosphorus oxyhalide derivative represented by the general formula (III) used in the method for producing the novel dehydration condensation agent of the present invention is exemplified below.

Examples thereof include phosphorus oxychloride, phosphorus oxybromide, phosphorus oxyiodide and the like.

The dehydration-condensation agent of the present invention is generally a primary or secondary ester of various alcohols and carboxylic acids such as esters and lactones.
Amides, peptides, lactams, etc. from primary amines and carboxylic acids, various thioesters, sulfonates,
It can be used for the synthesis of sulfonamide, sultone, sultam and the like.

When the dehydration-condensation agent of the present invention is used in the condensation reaction, the reaction can be advanced in a more quantitative yield.

The dehydration condensing agent of the present invention can be easily removed after the reaction by washing the water adduct of the present agent formed with water or a weak alkaline aqueous solution, and is highly safe from the viewpoint of the reaction operation. It is a dehydration condensing agent.

The dehydrating condensing agent is a stable crystalline compound and can withstand isolation and long-term storage.

Further, this reaction agent is not only a dehydrating agent but also a primary or secondary agent.
It is also useful as a phosphorylating agent for alcohols containing a primary hydroxyl group.

{T. Nagamatsu and T. Kunieda, Tetrahedron Lett. , 2
8 , 2375 (1987). Examples [Examples] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

(Example 1) The production of the dehydration condensation agent tris (2-oxo-3-oxazolinyl) phosphine oxide of the present invention will be described.

To a vigorously stirred suspension of 2-oxazolone (12.76g.0.15mol) in dry methylene chloride (280ml) under water cooling,
After adding phosphorus oxychloride (10.73 g, 0.07 mol), a solution of triethylamine (20.20 g, 0.20 mol) in dry methylene chloride (20 ml) was added dropwise.

The reaction mixture was stirred at room temperature for 15 hours, the generated crystals were filtered, washed with hot methylene chloride and recrystallized from ethyl acetate to give the title compound (9.50 g) as colorless granular crystals.

Further, the liquid and the washing liquid were concentrated to dryness, and the residue was subjected to silica gel column chromatography (200 g of silica gel) using ethyl acetate as an elution solvent to obtain a further 6.50 g of the title compound. The total yield was 16.00 g (76.4%).

 The obtained title compound had an mp. 164-167 ° C.

Elemental analysis results C ₉ H ₆ N ₃ O ₇ P theoretical value C, 36.14; H, 2.02; N, 14.05 (%) analytical value C, 36.41; H, 1.95; N, 14.17 (%) (Example 2) The method for producing the dehydration condensation agent tris (2-oxo-3-benzoxazolinyl) phosphine oxide of the present invention will be described.

To a solution of 2-benzoxazolinone (20.27 g, 0.15 mol) in dry methylene chloride (300 ml) was added phosphorus oxychloride (7.82 g, 0.05 mol) under ice cooling, and then triethylamine (15.38 g, 0.15 mol) was added at the same temperature. Mol of dry methylene chloride (20m
l) The solution was added dropwise. The reaction mixture was stirred at room temperature for 20 hours, the resulting insoluble material was removed, and the liquid was concentrated to dryness.

The residue was subjected to silica gel column chromatography (silica gel 250 g) using methylene chloride as an elution solvent to obtain 16.50 g (72.0%) of the title compound as colorless prism crystals.

 The mp. Of the obtained compound was 251-252 ° C.

Elemental analysis results C ₂₁ H ₁₂ N ₃ O ₇ P Theoretical value C, 56.14; H, 2.69, N, 9.35 (%) Analytical value C, 56.34; H, 2.64, N, 9.37 (%) (Example 3) In this example, a condensation reaction using the dehydration condensation agent of the present invention will be described as an example. That is, an example of producing N-benzyl-3-propanelactam using the dehydration condensing agent of the present invention is shown.

N-benzyl-3-aminopropionic acid (0.36 g, 2.0
Mmol) and tris (2-oxo-3) as a dehydration condensing agent
-Oxazolinyl) phosphine oxide (0.54 g, 2.0 mmol) was used and triethylamine (0.61 g, 0.60 mmol) was added to a solution of this in acetonitrile (200 ml).

After the reaction mixture was heated under reflux for 6 hours, acetonitrile was distilled off under reduced pressure, the residue was dissolved in methylene chloride (30 ml) and washed with water.

 The organic layer was separated and concentrated to dryness.

The residue was subjected to silica gel column chromatography (silica gel 30 g, eluted with methylene chloride: ethyl acetate = 7: 1) to obtain 0.31 g (96%) of N-benzyl-3-propanelactam as a colorless oily substance. Consistency of physical property values and analytical data with a standard compound (Authentic sample) was confirmed. (See J. Am. Chem. Soc. , 103 , 2406 (1981)} (Examples 4,5, 6, 7) By the same method as in Example 3, the dehydration condensation agent tris (2-oxo-3) of the present invention was used. -Oxazolinyl) phosphine oxide was used to synthesize β-lactams shown in Table 1 below.

(Example 8) Tris (2-oxo-3-) as a dehydration condensation agent of the present invention
Oxazolinyl) phosphine oxide was used and applied to the next condensation reaction.

 The following three compounds were used as comparative examples.

 The results are shown in Table 2.

(Remarks) (a) Proceedings of the Kyushu Chapter Meeting of the Pharmaceutical Society of Japan , p.
16 (1987) (b) Chem, LETT ., 659 (1985) [Effect of the Invention] The dehydration condensing agent of the present invention is an ester, a lactone, an amide,
It can be used for a condensation reaction in the synthesis of peptides, lactams, various thioesters, sulfonic acid esters, sulfonamides, sultones, sultams and the like.

The first advantage of the dehydration-condensation agent of the present invention is that the condensation reaction can be proceeded in a higher yield, closer to a quantitative yield, and has a wider application range than conventional condensing agents.

The second advantage is that it is extremely easy to remove the water adduct of the present dehydration condensation agent after the reaction from the reaction system.

The third advantage is that the dehydration condensing agent is highly safe in the reaction operation.

The fourth advantage is that the present dehydration condensation agent is a stable crystalline compound, is easy to isolate, can withstand long-term storage, and can be used industrially.

The fifth advantage is that the present reaction agent is not only used as a dehydrating agent,
It is also useful as a phosphorylating agent for alcohols containing primary or secondary hydroxyl groups.

Also as a production method, an easily available raw material can be used for production under mild reaction conditions.

The present invention is a major invention that contributes to the organic synthesis reaction.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 499/86 9159-4C C07D 205/08 K 499/87 499/00 A 499/893 Z 499 / 897 499/06

Claims (2)

(57) [Claims] 1. A dehydration condensing agent represented by the general formula (I). However, in the formula (I), L is a formula: Indicates a group. [In the formula L, X ¹ and X ² are each independently a hydrogen atom,
A lower alkyl group having 1 to 5 carbon atoms or a halogen atom, a nitro group, a group of -COOR ¹ (R ¹ represents a lower alkyl group having 1 to 4 carbon atoms), or X ¹ and X ² together Nari expression: {In the formula, X ³ and X ⁴ are, independently of each other, a hydrogen atom and a carbon number of 1 to 1.
A lower alkyl group of 4, or a halogen atom, a nitro group,
R ² SO ₂ — group (R ² is a lower alkyl group having 1 to 4 carbon atoms or an aryl group). } Is represented. ] 2. A 2-oxazolone derivative represented by the general formula (II): [Wherein, in the formula (II), X ¹ and X ² are each independently a hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, a halogen atom, a nitro group, —COOR ¹ (R ¹ is 1 to 4 carbon atoms) Represents a lower alkyl group), or X ¹ and X ² are taken together to form the formula: {In the formula, X ³ and X ⁴ are each independently a hydrogen atom or a carbon number of 1 to 4
Lower alkyl group, halogen atom, nitro group, R ²
Represents a SO ₂ — group (R ² represents a lower alkyl group having 1 to 4 carbon atoms or an aryl group). }. ] The phosphorus oxyhalide represented by the general formula (III) (In the formula, Hal represents a halogen atom.) The reaction is carried out in the presence of a base, the general formula (I) according to claim 1. A method for producing a dehydration condensing agent represented by.