CN1629184A - N-acyl-aspartic acid-beta-dipeptide derivatives preparing process - Google Patents
N-acyl-aspartic acid-beta-dipeptide derivatives preparing process Download PDFInfo
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Abstract
The invention provides an N-acyl-aspartic acid-beta-dipeptide derivatives preparing process which comprises, preparing N-acyl-(S)-4-benzyloxy carbonyl azetidine-2-ketone (2), dissolving (S)-4-benzyloxy carbonyl azetidine-2-ketone (1) into DMF to obtain solution, dropping in spasmolytol, charging acylating agent, after reacting, carrying out extracting, scouring, drying, chromatography purifying to obtain (2), preparing N-acyl-aspartic acid-beta-dipeptide derivatives, dissolving (2) into DMF to prepare solution, charging amino acid ester and catalyst, after reaction, carrying out extraction, scouring, drying, chromatography purifying to obtain the end product.
Description
Technical field
The present invention relates to a kind of synthetic method of peptide compounds, especially a kind of preparation method of N-acyl-aspartic acid-beta-dipeptide derivatives.
Background technology
Peptide is the compound that a class has important use, and many peptides are important drugs of treatment various diseases.Synthetic and the physiologically active screening of peptide is an important research field of new drug development.The formation of peptide normally forms peptide bond and (sees document S.-Y.Han on amino acid whose alpha-position; Y.-A.Kim; tetrahedron; 2004; 60:2447-2467); the amino acid that contains two carboxyls as the β of aspartic acid or L-glutamic acid-or γ-position on form and need protect the amino acid that becomes peptide the peptide; utilize linked reaction will protect amino acid to connect into peptide then, also need remove blocking group at last, just can obtain desired peptide and (see document F.Itoh; Y.Yoshioka; et al, Chem .Pharm.Bull; 1996,44:1498-1509).This one-tenth peptide method steps is loaded down with trivial details, efficient is low, and may be owing to coupling condition produces the part racemization.
Summary of the invention
The present invention aims to provide a kind of method of simple and convenient, high efficiency synthetic N-acyl-aspartic acid-beta-dipeptide derivatives.This new method need not be used coupling reagent; the racemization of peptide can not take place; and reduced the use of blocking group; peptide formation has good position specific simultaneously; reaction conditions gentleness, yield height, easy handling are a kind of convenience, economy, the method for synthetic aspartic acid-beta-dipeptidase derivant efficiently.
Chemical equation of the present invention is as follows:
The steps include:
Step 1: preparation N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2)
Under nitrogen atmosphere, with (S)-azetidinone-4-benzyl carboxylate (1) stirring and dissolving in dimethyl formamide (DMF), make 0.2～1.5 mol, the solution of 0.8～1.1 mol preferably, after being cooled to 0 ℃ with ice-water bath, be added dropwise to and be equivalent to (1) 0.8～1.8, preferably the triethylamine of 1.1～1.5 times of molar weights; Add again and be equivalent to (1) 0.8～1.5; the acylating reagent of 1.1～1.3 times of molar weights preferably; said acylating reagent is meant the acid anhydrides of C2～C5; the acyl chloride of C2～C5; the acid anhydrides of benzene, the acyl chloride of benzene, the acid anhydrides of toluene; the acyl chloride of toluene, the sulfonyl chloride of benzene or the sulfonyl chloride of substituted benzene.Reaction mixture rise to room temperature and continue to be stirred to react completely after; in reaction mixture, add saturated aqueous common salt and ethyl acetate; tell organic layer; the water layer ethyl acetate extraction; merge organic layer; water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying steams and to desolventize the back head product and get N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) through purification by silica gel column chromatography.
Step 2: preparation N-acyl-aspartic acid-beta-dipeptide derivatives
Under nitrogen atmosphere, with N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) stirring and dissolving in DMF, make 0.2～1.2 mol, the solution of 0.5～0.8 mol preferably, add successively and be equivalent to (2) 0.8～1.5 times, the preferably amino acid ester of 1.1～1.3 times of molar weights and be equivalent to (2) 5%～20% moles, preferably a kind of catalyzer of 8%～12% mole; Said catalyzer is the sodium salt of lower alcohol, alkali metal cyanide or trinitride, the sodium salt of the alcohol of C1～C3 preferably, the prussiate of potassium, the prussiate of sodium or trinitride.Reaction mixture at room temperature is stirred to (2) and reacts completely.In reaction mixture, add saturated aqueous common salt and ether; tell organic layer; the water layer extracted with diethyl ether; merge organic layer; water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get N-acyl-aspartic acid-beta-dipeptide derivatives (3) through purification by silica gel column chromatography.
(S)-and azetidinone-4-benzyl carboxylate (1) is a kind of new chiral building block, it can obtain from (S)-aspartic acid is synthetic easily.Because (1) is the aspartic acid of protection in form, its lactan nitrogen carried out acidylate after, in the presence of catalyzer, react with the amino acid of carboxy protective, can form dipeptides easily, be a kind of effective ways that contain aspartic acid-beta-dipeptides that synthesize.The method of formation aspartic acid-beta-dipeptides that this is new need not to use coupling reagent; thereby racemization can not take place; also reduced simultaneously the use of blocking group; and peptide formation betides on the β-carboxyl of aspartic acid single-mindedly; only need single step reaction to get final product high yield (75%～95%) and obtain the diversified β-dipeptidase derivant that contains aspartic acid of structure; simplified synthesis step greatly; having improved combined coefficient, is a kind of economy, effective novel method of synthetic aspartic acid-beta-dipeptidase derivant efficiently.
Embodiment
The embodiment that below provides will the present invention is further illustrated.
Embodiment 1:
Under nitrogen atmosphere; with (410 milligrams of (S)-carbobenzoxy-(Cbz) azetidines-2-ketone (1); 2 mmoles) be dissolved among the dry DMF; make the solution that concentration is 0.2 mole/L; after being cooled to 0 ℃ with ice-water bath, be added dropwise to the triethylamine of 1.6 moles of multiples of reactant (1), adding consumption then is the acylating reagent diacetyl oxide of 1.2 moles of multiples of reactant (1); stir after 20 minutes, rise to room temperature and continue to be stirred to and react completely.The ethyl acetate that adds isopyknic saturated aqueous common salt and 1～3 times in the reaction mixture; tell organic layer after the stirring; the water layer equal volume of ethyl acetate; merge organic layer; water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get (N-acyl group)-(S)-carbobenzoxy-(Cbz) azetidine-2-ketone (2) through quick purification by silica gel column chromatography.
Preparation [(N-benzoyl)-L-aspartic acid-α-benzyl ester-β-acyl group]-L-alanine methyl ester:
Under nitrogen atmosphere; will be in dry DMF by the above-mentioned N-acyl group that makes-(S)-carbobenzoxy-(Cbz) azetidine-2-ketone (2) (1 mmole) stirring and dissolving; make the solution that concentration is 0.4 mole/L; the adding consumption is that the glycine ethyl ester and the consumption of 1.5 moles of multiples of reactant (2) is the catalyzer sodium methylate of 9% molecular fraction of reactant (2), and reaction mixture at room temperature stirs reasonable time.In reaction mixture, add saturated aqueous common salt and ether then; tell organic layer after the stirring; the water layer extracted with diethyl ether; merge organic layer; water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get N-acyl group-L-aspartic acid-beta-dipeptidase derivant through quick purification by silica gel column chromatography.
Embodiment 2:
Similar with the processing step of embodiment 1; its difference is under nitrogen atmosphere; with (410 milligrams of (S)-carbobenzoxy-(Cbz) azetidines-2-ketone (1); 2 mmoles) be dissolved among the dry DMF, make the solution that concentration is 0.4 mole/L, be cooled to 0 ℃ with ice-water bath after; be added dropwise to the triethylamine of 0.8 mole of multiple of reactant (1); adding consumption then is the acylating reagent propionyl chloride of 1.3 moles of multiples of reactant (1), stirs after 20 minutes, rises to room temperature and continue to be stirred to react completely.The ethyl acetate that adds isopyknic saturated aqueous common salt and 2 times in the reaction mixture; tell organic layer after the stirring; the water layer equal volume of ethyl acetate; merge organic layer; water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get (N-acyl group)-(S)-carbobenzoxy-(Cbz) azetidine-2-ketone (2) through quick purification by silica gel column chromatography.
Preparation [(N-benzoyl)-L-aspartic acid-α-benzyl ester-β-acyl group]-L-alanine methyl ester:
Under nitrogen atmosphere; will be in dry DMF by the above-mentioned N-acyl group that makes-(S)-carbobenzoxy-(Cbz) azetidine-2-ketone (2) (1 mmole) stirring and dissolving; make the solution that concentration is 1.1 moles/L; the adding consumption is that the L-L-Ala tert-butyl ester and the consumption of 0.9 mole of multiple of reactant (2) is the catalyzer sodium ethylate of 8% molecular fraction of reactant (2), and reaction mixture at room temperature stirs reasonable time.In reaction mixture, add saturated aqueous common salt and ether then; tell organic layer after the stirring; the water layer extracted with diethyl ether; merge organic layer; water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get N-acyl group-L-aspartic acid-beta-dipeptidase derivant through quick purification by silica gel column chromatography.
Embodiment 3-10:
The processing step of preparation N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) is similar to Example 1, and its difference is the concentration of the reactant (1) made, consumption, acylating reagent and the consumption thereof of triethylamine, sees table 1 for details.
Table 1
| Embodiment | The concentration (mol) of reactant (1) | The consumption of triethylamine (the mole multiple of reactant (1)) | Acylating reagent | The consumption of acylating reagent (the mole multiple of reactant (1)) |
| ??3 | ??0.5 | ??1.4 | Pivaloyl chloride | ??1.0 |
| ??4 | ??0.8 | ??1.2 | Two tert.-butoxy carbonic anhydrides | ??0.9 |
| ??5 | ??0.9 | ??1.1 | Benzoyl oxide | ??1.5 |
| ??6 | ??1.0 | ??1.0 | Tetra hydro Phthalic anhydride | ??1.1 |
| ??7 | ??1.1 | ??1.3 | Benzoyl chloride | ??1.2 |
| ??8 | ??1.2 | ??1.4 | Chloroformic acid benzyl ester | ??0.8 |
| ??9 | ??1.3 | ??1.8 | Benzene sulfonyl | ??1.1 |
| ??10 | ??1.5 | ??1.0 | To methylsulfonyl chloride | ??1.3 |
The processing step of preparation [(N-benzoyl)-L-aspartic acid-α-benzyl ester-β-acyl group]-L-alanine methyl ester is similar to Example 1, and its difference is concentration, amino acid ester and consumption thereof and the catalyzer and the consumption thereof of reactant (2), sees table 2 for details.
Table 2
| Embodiment | The concentration (mol) of reactant (2) | Amino acid ester | The consumption of amino acid ester (the mole multiple of reactant (2)) | Catalyzer | Catalyst consumption (molecular fraction of reactant (2)) |
| ?3 | ?0.5 | L-leucine benzyl ester | ??1.3 | The sodium propylate sodium cyanide | 12 |
| ?4 | ?0.8 | The L-L-Tyrosine methyl ester | ??1.1 | Potassium cyanide | 16 |
| ?5 | ?0.7 | (S)-1-amino-cyclopropane-1-carboxylic acid, ethyl ester | ??1.2 | Sodiumazide | 7 |
| ?6 | ?1.0 | (2R, 3S)-1-aminocyclohexane-1-carboxylic acid, ethyl ester | ??0.8 | Sodium ethylate | 5 |
| ?7 | ?1.2 | D-phenylglycine ethyl ester or L-methionine(Met) ethyl ester | ??1.0 | Potassium cyanide | 10 |
| ?8 | ?0.6 | (S)-4-phenyl Gamma Amino Butyric Acid ethyl ester | ??1.2 | Sodium methylate | 20 |
| ?9 | ?0.9 | (R)-1-aminocyclohexane-1-carboxylic acid, ethyl ester | ??1.1 | The sodium propylate sodium cyanide | 18 |
| ?10 | ?0.7 | The L-ethyl prolinate | ??1.3 | Sodiumazide | 8 |
Claims (8)
1, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method is characterized in that the chemical equation of preparation process is as follows:
2, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method is characterized in that the steps include:
1) preparation N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2)
Under nitrogen atmosphere, (S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (1) stirring and dissolving in dry DMF solvent, is made the solution of 0.2～1.5 mol, be cooled to 0 ℃ with ice-water bath after, be added dropwise to the triethylamine that is equivalent to (1) 0.8～1.8 molar weight; Add the acylating reagent that is equivalent to (1) 0.8～1.5 times of molar weight again, said acylating reagent refers to acid anhydrides or the acyl chlorides of C2～C5, the acid anhydrides of benzene and toluene, the sulfonyl chloride of acyl chloride and benzene and substituted benzene, reaction mixture stirs and rises to room temperature to reacting completely, in reaction mixture, add saturated aqueous common salt and ethyl acetate, tell organic layer after the stirring, the water layer ethyl acetate extraction, merge organic layer, water and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying steams and to desolventize the back head product and get N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) through purification by silica gel column chromatography;
2) preparation N-acyl-aspartic acid-beta-dipeptide derivatives
Under nitrogen atmosphere, with N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) stirring and dissolving in dry DMF solvent, make the solution of 0.2～1.2 mol, add the amino acid ester that is equivalent to (2) 0.8～1.5 times of molar weights successively and be equivalent to (2) 5%～12% moles catalyzer; Said catalyzer is sodium or sylvite, alkali metal cyanide or the trinitride of lower alcohol; reaction mixture at room temperature is stirred to (2) and reacts completely; in reaction mixture, add saturated aqueous common salt and ether; tell organic layer after the stirring; the water layer extracted with diethyl ether merges organic layer, water and saturated common salt water washing successively; organic layer anhydrous magnesium sulfate drying, steaming desolventize the back head product and get the N-acyl-aspartic acid-beta-dipeptide derivatives through purification by silica gel column chromatography.
3, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2; it is characterized in that in step 1; under nitrogen atmosphere, (S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (1) stirring and dissolving in dry DMF solvent, is made the solution of 0.8～1.1 mol.
4, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2 is characterized in that in step 1, be cooled to 0 ℃ with ice-water bath after, be added dropwise to the triethylamine that is equivalent to (1) 1.1～1.5 molar weight.
5, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2 is characterized in that in step 1, adds the acylating reagent that is equivalent to (1) 1.1～1.3 molar weight again.
6, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2; it is characterized in that in step 2; under nitrogen atmosphere; N-acyl group-(S)-4-carbobenzoxy-(Cbz) azetidine-2-ketone (2) stirring and dissolving in dry DMF solvent, is made the solution of 0.5～0.8 mol.
7, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2 is characterized in that in step 2, adds the amino acid ester that is equivalent to (2) 1.1～1.3 times of molar weights successively and is equivalent to (2) 8%～20% moles catalyzer.
8, N-acyl-aspartic acid-beta-dipeptide derivatives preparation method as claimed in claim 2 is characterized in that in step 2, and said catalyzer is the prussiate or the trinitride of the sodium of alcohol of C1～C3 or sylvite, sodium, the prussiate of potassium.
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