JPH06116228A - Carbodiimide derivative and method for producing the same - Google Patents

Abstract

Carbodiimide derivative according to (57) [Abstract] [Configuration] The present invention is a compound represented by ^{R 1 -N = C = N- (} CH 2) n -OCH 3 ... ( Formula I). (However, in the above formula, R ¹ is a lower alkyl group, and n is 2 or 3.) [Effect] The carbodiimide derivative of the present invention is excellent in storage stability, less toxic to the human body, and liquid. Because of this, handling in the process is easy. Moreover, since a highly pure dehydration condensate can be obtained in a high yield, it is particularly useful in the field of ultraprecision organic synthesis.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carbodiimide derivative and a method for producing the same, more specifically, a novel carbodiimide preferably used for the synthesis of protein, peptide, sugar, nucleic acid or amide bond or ester bond in the field of general organic synthesis. Derivatives and methods for producing the same.

[0002]

BACKGROUND OF THE INVENTION In the fields of proteins, peptides, sugars, nucleic acids, and general organic synthesis, many reagents which form an amide bond by dehydration condensation of one molecule from a carboxyl group and an amino group are known to date. In particular, the dehydration condensation reaction with a carbodiimide derivative can be advanced under mild conditions, and is therefore widely used especially in the field of precision organic synthetic chemistry for biological material systems. Typical examples thereof include (i) dicyclohexylcarbodiimide (hereinafter abbreviated as DCC), diisopropylcarbodiimide, etc., or (ii) 1-ethyl-3- (3-N, N-dimethylaminopropyl) -carbodiimide (hereinafter EDC). Or its hydrochloride, or 1-cyclohexyl
-3- (2-morpholinoethyl) -carbodiimide or its
Examples include p-toluenesulfonic acid methyl ester.

As typical examples of the carbodiimides exemplified in (i) and (ii) above, the use conditions of DCC and EDC and their problems will be described below. Although DCC is inexpensive and easily available as an industrial material, it is cumbersome to handle when used in large quantities because the product form is lumpy. In addition, since the DCC-derived urea body generated as a reaction by-product in dehydration condensation using DCC is poorly water-soluble,
When a non-hydrophilic organic solvent is used as the reaction solvent, it is difficult to remove it by washing with water. Therefore, when a non-hydrophilic organic solvent is used, the urea body is replaced with a solvent having a low solubility, precipitated as urea crystals, and a method of filtering off is generally performed. The method is complicated in process and cannot completely remove the urea form. As a result, the purity of the final product is lowered, which becomes a big problem in the field of ultra-precision organic synthesis, which requires ever higher purity. Furthermore, since DCC causes "rash" on the skin of the human body, it is very problematic in terms of occupational hygiene, and particularly when it is used on an industrial scale, strict consideration for safety is required.

On the other hand, since EDC is soluble in water and an organic solvent, and the urea by-product of the reaction is soluble in water, the above-mentioned process problems do not occur. However, conventionally used carbodiimides represented by EDC have problems in storage stability. Further, since the synthetic raw materials are extremely expensive and the reaction synthetic yield is not sufficient, the price per EDC product unit price was high. Therefore, although EDC has various process advantages, it cannot be used on an industrial scale.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned prior art, and can be manufactured economically, has excellent storage stability, is easy to handle in the process, and An object of the present invention is to provide a carbodiimide derivative capable of obtaining a dehydration condensate, which is a target product, in high yield and high purity, and a method for producing the same.

[0006]

Carbodiimide derivative of the present invention SUMMARY OF THE INVENTION are the compounds represented by ^{R 1 -N = C = N- (} CH 2) n -OCH 3 ... ( Formula I). (However, in the above formula, R ¹ is a lower alkyl group, and n is 2 or 3.) The first method for producing a carbodiimide derivative according to the present invention is R ¹
An isocyanate represented by —NCO (wherein R ¹ represents a lower alkyl group) and H ₂ N— (CH ₂ ) _n —O.
A urea derivative represented by R ¹ —NH—CO—NH— (CH ₂ ) _n —OCH ₃ (Formula II) by reacting with an amine represented by CH ₃ (where n is 2 or 3). Is synthesized, optionally isolated and purified, and then dehydrated to produce a compound represented by the above (formula I).

Second carbodiimide derivative according to the present invention
Method of manufacturing isothiocyanate represented by R ¹ -NCS (provided that, R ¹ represents a lower alkyl group.) And H
₂ N-(CH ₂₎ amine represented by _n -OCH ₃ (where, n is 2 or 3.) And reacted ^{to, R 1 -NH-CS-NH-} (CH 2) n -OCH 3 ... It is characterized in that the thiourea derivative represented by the formula (III) is synthesized, and if necessary, isolated and purified, and then desulfurized to produce the compound represented by the formula (I).

[0008]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in more detail below. Carbodiimide derivative of the present invention is a compound represented by ^{R 1 -N = C = N- (} CH 2) n -OCH 3 ... ( Formula I).

Here, R ¹ is a lower alkyl group, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an iso-butyl group, a tert-butyl group and the like having 1 carbon atom. ~ 4 straight or branched saturated hydrocarbon groups. Among these, an ethyl group is preferable.

Further, n represents an integer of 2 or 3. The structure and composition of the carbodiimide derivative according to the present invention are as follows: infrared absorption analysis (IR), nuclear magnetic resonance analysis (N
It is confirmed by methods such as MR) and elemental analysis.

The boiling point of the carbodiimide derivative of the present invention is 3
It is about 0 to 70 ° C. (1 to 10 mmHg), and is liquid at normal temperature. Therefore, the operation is easy even when handling a large amount. Further, as is clear from the chemical structural formula, since it has a lower alkyl group and a methoxy group and is neutral, the solubility of the urea by-product of the reaction in an organic solvent is high.
Therefore, when the reaction target product is obtained in crystalline form, it is possible to obtain a high-purity target product by treating and washing with a solvent that dissolves the urea body without dissolving the target product. Further, since the urea body is also dissolved in a dilute acidic aqueous solution, the urea body can be removed even when the target product is oily.

The carbodiimide derivative is a stable compound for a long period of time when stored in a refrigerator. Further, this compound, like DCC described above, has less "rash" on the human body and contributes to the improvement of the occupational health environment.

When the carbodiimide derivative of the present invention is used as a dehydration condensation agent in peptide synthesis, the dehydration condensation reaction can proceed under extremely mild conditions.
Moreover, it is possible to take out the target product with high yield and high purity without causing racemization. Therefore, it is expected to make a great contribution in the field of ultra-precision organic synthesis, which requires ever higher purity.

Furthermore, since the carbodiimide of the present invention is in a liquid state as described above and has a high solubility of the by-product urea compound in an organic solvent, it is optimal for solid phase peptide synthesis.

The carbodiimide derivative of the present invention is used, for example, in addition to the above-mentioned use as a dehydration condensation agent, for example, as an oxidation reaction auxiliary agent, polymer synthesis-related, polymerization-acceleration-related, dye industry, photographic industry, herbicide, insecticide, Applications are expected to expand in the field of fungicides.

The carbodiimide derivative of the present invention is
Existence as a complex compound is also allowed. Further, in the production of the carbodiimide derivative of the present invention, starting materials are easily available, and the production process is relatively simple as will be described later, which is significantly advantageous in the process as compared with the production of DCC or EDC. .

Next, a method for producing the carbodiimide derivative of the present invention will be described. I. Synthesis of Urea Derivative or Thiourea Derivative In the present invention, first, alkyl isocyanate R ¹
NCO or alkyl isothiocyanate R ¹ NCS
(R ¹ is a lower alkyl group) and amine H ₂ N-
A urea derivative or a thiourea derivative is synthesized by a reaction with (CH ₂ ) _n —OCH ₃ (n is an integer of 2 or 3).

R ¹ is, similarly to the above, a straight chain or branched saturated hydrocarbon group having 1 to 4 carbon atoms, particularly an ethyl group,
It is preferable in terms of obtaining raw materials and sufficiently exhibiting the effects of the present invention.

In the following description, alkyl isocyanate or alkyl isothiocyanate is used as R ¹
It may be abbreviated as NCX (X represents an oxygen atom or a sulfur atom).

Specific examples of the amine represented by H ₂ N- (CH ₂ ) _n -OCH ₃ (n is an integer of 2 or 3) are 2-methoxy-ethylamine and 3-methoxy-propylamine,
It is easily available as an industrial material.

The reaction of R ¹ NCX with an amine is described below (formula I
V). _{^{R 1 NCX + H 2 N- (}} CH 2) n -OCH 3 → R 1 -NH-CX-NH- (CH 2) n -OCH 3 ... ( Formula IV) alkyl isocyanate or alkyl isothiocyanate 1 mol per amine Is used in an amount of 1.0 to 1.2 mol. This reaction is usually performed in an organic solvent at 1
It is carried out under cooling or at room temperature for a time of 24 hours.

The organic solvent used is appropriately selected within a range that does not adversely affect the reaction, but halogenated hydrocarbons, ethers, hydrocarbon-based esters and the like are preferable.
As a result of the above reaction, a urea form or a thiourea form is usually obtained with a yield of 90 to 100%.

The synthesized urea form or thiourea form is isolated and purified by an appropriate method, if necessary, and subjected to the carbodiimidization reaction in the next step. Isolation and purification are not always necessary, and it is possible to continuously shift to the carbodiimidization reaction step without isolation and purification. Industrially, the continuous method is advantageous. II. Carbodiimidization reaction step The urea derivative or thiourea derivative synthesized above is
A carbodiimide derivative is obtained by a dehydration reaction or a desulfurization hydrogenation reaction to obtain a carbodiimide derivative (formula V).

[0024]

[Chemical 1]

The reaction conditions are not particularly limited, but usually, in an organic solvent such as a halogenated hydrocarbon, 0 ° C to 8 ° C.
It is carried out at a temperature of 0 ° C. for 1 to 24 hours. It is particularly preferable to carry out this reaction in the presence of a dehydrating agent or a desulfurizing agent.

For example, [p-toluenesulfonic acid chloride / pyridine], [p-toluenesulfonic acid chloride / triethylamine], [phosphorus pentoxide / pyridine], or the like is used for dehydration of the urea derivative.

Further, the desulfurized hydrogen of the thiourea derivative includes
[Hypochlorous acid / caustic soda], mercury oxide, lead oxide and the like are used.

[0028]

EFFECTS OF THE INVENTION The carbodiimide derivative of the present invention is excellent in storage stability, has less "rash" on the human body, and is easy to handle in the process because it is liquid.
Moreover, since a highly pure dehydration condensate can be obtained in a high yield, it is particularly useful in the field of ultraprecision organic synthesis. Further, according to the production method of the present invention, the above carbodiimide derivative can be produced economically.

[0029]

EXAMPLES Examples according to the present invention will be specifically described below, but the present invention is not limited to the following examples.

[0030]

Example 1 [Synthesis of 1-ethyl-3- (2-methoxyethyl) -carbodiimide] 2-Methoxyethylamine while stirring 35.5 g (0.5 mol) of ethyl isocyanate and 500 ml of dichloromethane at 10 ° C. or lower with stirring. 37.6 g (0.5 mol) was gradually added dropwise, and the mixture was reacted at the same temperature for 1 hour, and then the reaction was continued at room temperature for 12 hours to synthesize 1-ethyl-3- (2-methoxyethyl) urea.

The above reaction solution was cooled to 10 ° C. or lower with stirring, triethylamine was added, and then 105 g (0.55 mol) of p-toluenesulfonic acid chloride and dichloromethane were added.
A homogeneous solution of 180 ml was added dropwise at the same temperature. afterwards,
After refluxing for 5 hours and allowing to cool, 118 g of sodium carbonate and 600 water
It was added to a solution of ml and the dichloromethane layer was separated. The aqueous layer was extracted again with 400 ml of dichloromethane, both dichloromethane layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off with an evaporator, and the residue was vacuum distilled to obtain 77 g of a liquid target product (yield 60%). ) Got.

The boiling point is 48 to 50 ° C./1.5 mmHg, and the result of infrared absorption analysis (IR) is 2130 cm ^-1 (-
Absorption due to N = C = N-) binding was seen.

[0033]

Example 2 [Synthesis of 1-ethyl-3- (3-methoxypropyl) -carbodiimide] 1-Ethyl-3- (3-methoxypropyl) urea synthesized and purified from ethylisocyanate and 3-methoxypropylamine 80 g was dissolved in 500 ml dichloromethane,
While cooling and stirring, 200 ml of pyridine was added, then 120 g of p-toluenesulfonic acid chloride and 200 ml of dichloromethane.
A homogeneous solution with ml was added dropwise. After refluxing for 6 hours, the mixture was allowed to cool, the reaction solution was added to a solution consisting of 180 g of sodium carbonate and 1600 ml of water, and the dichloromethane layer was separated.

The aqueous layer was extracted again with 400 ml of dichloromethane, both dichloromethane layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was vacuum distilled to obtain 107 g of the target product in a liquid state (75%, urea standard). ).

The boiling point is 49 to 53 ° C./4 mmHg,
As a result of infrared absorption analysis (IR), at 2130 cm ^-1 (-N =
Absorption due to the C = N-) bond was seen.

[0036]

[Reference example]

[N-tert-butoxycarbonyl-L-phenylalanyl-L-
Synthesis of leucine ethyl ester] N-tert-butoxycarbonyl-L-phenylalanine 20 g (75.4 mmol), L
14.8 g (75.4 mmol) of leucine ethyl ester hydrochloride was dissolved in 100 ml of DMF and cooled to below 0 ° C.
8.3 ml (75.4 mmol) of N-methylmorpholine and HO
10.2 g (75.4 mmol) of Bt was added. Further, 10.7 g (75.4 mmol) of 1-ethyl-3- (3-methoxypropyl) carbodiimide obtained in Example 2 was added. After cooling and stirring for 2 hours, the mixture was stirred at room temperature overnight.

The reaction solution was poured into cold water and extracted with ethyl acetate. The organic layer was washed several times with 1M-hydrochloric acid water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 27.6 g (yield 90%) of the title peptide as crystals.

The melting point of the obtained peptide is 115-116.
C, and its specific rotation [α] _D ²⁰ is −25.5 (C =
0.5, MeOH). The results of ¹ H-NMR analysis are shown below.

¹ H-NMR δ (CDCl ₃ ) 0.91 (6H, t) 1.26 (3H, t) 1.41 (9H, s) 1.55 (2H, m) 1.74 (1H, m) 3.07 (2H, d) 4.15 (2H, q) 4.36 (1H, dt) 4.53 (1H, m) 5.01 (1H, d) 6.29 (1H, d) 7.20-7.33 (5H, m)

Claims (5)

[Claims] 1. R ¹ -N = C = N- (CH ₂ ) _n- OC
A carbodiimide derivative represented by H ₃ ... (Formula I). (However, in the above formula,
R ¹ is a lower alkyl group and n is 2 or 3. ) 2. The carbodiimide derivative according to claim 1, wherein R ¹ is an ethyl group. 3. An isocyanate represented by R ¹ -NCO (wherein R ¹ represents a lower alkyl group) and H ₂ N.
An amine represented by — (CH ₂ ) _n —OCH ₃ (provided that
n is 2 or 3. ) To synthesize a urea derivative represented by R ¹ —NH—CO—NH— (CH ₂ ) _n —OCH ₃ ... (Formula II), and if necessary, isolated and purified, and then dehydrated, ^{R 1 -N = C = N- (} CH 2) n -OCH 3 ... carbodiimide derivative represented by (formula I) (where in the formula,
R ¹ is a lower alkyl group and n is 2 or 3. ) Is manufactured, The manufacturing method of the carbodiimide derivative characterized by the above-mentioned. 4. An isothiocyanate represented by R ¹ -NCS (wherein R ¹ represents a lower alkyl group) and H _2.
Amine represented by _{N- (CH 2) n -OCH 3} ( where, n is 2 or 3.) And reacted ^{to, R 1 -NH-CS-NH-} (CH 2) n -OCH 3 ... ( The thiourea derivative represented by the formula III) is synthesized, and if necessary, isolated and purified, and then desulfurized, and R ¹ —N═C═N— (CH ₂ ) _n —OCH ₃ ... (Formula I) A carbodiimide derivative represented by
R ¹ is a lower alkyl group and n is 2 or 3. ) Is manufactured, The manufacturing method of the carbodiimide derivative characterized by the above-mentioned. 5. The method for producing a carbodiimide derivative according to claim 3, wherein R ¹ is an ethyl group.