CN101186549B - Method for preparing amino acid by reducing ketoxime acid ester - Google Patents

Abstract

The invention relates to the technical field of chemical pharmacy and foodstuff, in particular to a novel preparation method of amino acid prepared by reduction of ketoxime acid ester. A reduction system of the invention, which consists of H2/Pd-C, Zn/AcOH, Zn/AcOH-Ac20, Zn-Fe/AcOH, Ni/KBH4, Al-Ni/NaOH, etc., can meet the requirement for reduction in neutral condition, alkaline condition and acidic condition; selection of different reduction systems can be completely dependent on different synthesis purposes; the ketoxime acid ester comprises alpha-ketoxime acid ester and non-alpha-ketoxime acid ester. The preparation method is characterized by wide application range, high synthesis yield, simple operation and wide application, and being more convenient for biological resolution, etc.

Description

The amino acid whose novel method of a kind of ketoxime acid ester reduction preparation

Technical field

The present invention relates to fields such as chemical industry, pharmacy and food, relate in particular to the amino acid whose novel method of a kind of ketoxime acid ester reduction preparation.

Background technology

Amino acid is a kind of crucial nutritive substance, is one of indispensable nutritive ingredient of organism, and amino acid also is widely used in industry such as food, pharmacy, feed simultaneously.

Amino acid comprises natural amino acid and alpha-non-natural amino acid two classes of forming organism and participating in biological metabolism.Alpha-non-natural amino acid generally is the result of artificial design.Along with the research of amino acid, polypeptide, the protein effect in vital movement is goed deep into day by day; the particularly discovery of increasing biologically active polypeptide; to amino acid; the amino acid whose demand that particularly contains special construction is increasing, and the new synthetic method of natural amino acid and alpha-non-natural amino acid is a very active research field.

Traditional amino acid whose synthetic mainly contain Bucherer method, Strecker method, Meerwein method, Gaudnry method, acetamino diethyl malonate method and acetyl glycine method etc.In these methods, though the technology that has is fairly simple, damage ratio is more serious, and is amino by halid replacement introducing; The technology that has has been selected comparatively expensive raw material such as phenylacetic aldehyde for use, and reaction scheme is longer, and yield is low, thereby has lost industrialized value; What also have has then used hypertoxic raw material prussiate, and not only Cao Zuo security has been subjected to challenge, and has the problems such as severe contamination of cyanide wastewater equally.In reported method, the versatility of acetamino diethyl malonate method reaction is better, and the introducing of its amino is to realize by the also original of oxime, but the building-up reactions route is longer, the selectivity of reacting in the building-up process is relatively poor, thereby makes productive rate be subjected to great influence.

Summary of the invention

Problem at existing among the existing amino acid preparation method the invention provides a kind of chemical reduction ketoxime acid ester and prepares amino acid whose novel method, and it has characteristics such as synthesis yield height, simple to operate, wide adaptability and the biological fractionation of being more convenient for.

Reduction comprises reduction systems such as Ni/KBH4 and Al-Ni/NaOH, can be satisfied with the alkaline condition reduction.The selection of different reduction systems can be dependent on different synthetic purposes fully, and this preparation method is with a wide range of applications.

Technical solution of the present invention is:

The amino acid whose novel method of a kind of ketoxime acid ester reduction preparation, reduction system is Ni/KBH4 and Al-Ni/NaOH, and described reduction system can be satisfied with the requirement of alkaline condition reductive, and described ketoxime acid ester is alpha-ketoxime acid ester and non-alpha-ketoxime acid ester two classes.

Reduction under the described alkaline condition may further comprise the steps:

1. in the reaction flask of being furnished with stirring, thermometer, add ketoxime acid ester and the Ni that is dissolved in methyl alcohol, slowly drip methyl alcohol and the 5mol/L NaOH solution of KBH4 then, between temperature of reaction 25-80 ℃.The mol ratio of ketoxime acid ester and KBH4 is 1: 0.3-1.5.Methyl alcohol is reaction solvent, and its amount is controlled at 55～80% of reaction volume.

2. by with the ketoxime acid ester mol ratio be that 1: 1～1.05 amount adds acetic anhydride and 1. in the reaction solution, down continues stirring reaction 30min～3h in room temperature condition to above-mentioned steps.

3. reaction solution concentrates, and reclaims methyl alcohol and acetic acid, adds acid in the residuum, and transferring pH is 3.5～5.0, promptly has product to separate out, and recrystallization obtains the pure product of N-acetylamino acid.

Wherein, described Ni is a kind of among non-crystalline state Ni and the Raney Ni.

Above-mentioned reduction step can also for: directly add acetic anhydride in step after 1., can realize amino acid whose acetylize, obtain the N-acetylamino acid.

Reduction under the described alkaline condition can also be following steps:

1. add naphthalene acetoxime acid 0.05mol in the reaction flask of the 250mL that is furnished with stirring, thermometer respectively, methyl alcohol 100mL adds 1.0g Raney Ni, slowly drips 10mL (5mol/L) the NaOH solution of 2.5g KBH4, keeps about 50 ℃ of temperature of reaction.

2. be added dropwise to complete the back and add 10mL acetic anhydride, stirring at room 2h.

3. the suction filtration reaction solution concentrates and reclaims methyl alcohol and acetic acid, adds 2% hydrochloric acid in the residuum and transfers pH to 4, separates out N-acetonaphthone L-Ala crude product, obtains N-acetonaphthone L-Ala product with 95% ethyl alcohol recrystallization.

Further, described ketoxime acid ester comprises methyl esters and ethyl ester, and amino acid comprises a-amino acid, beta-amino acids, gamma-amino acid and δ-amino acid; Wherein the aryl in the aryl alanine has comprised all carbocyclic aromatics and the heterocyclic arene and the corresponding substitutive derivative of phenyl ring.

On ordinary meaning, the ketoxime acid ester reduction can be reduced in different reduction systems.Wherein reductive condition such as RaneyNi/KBH4/H2O and non-crystalline state Ni/KBH4/H2O has good versatility, yield height not only, and also operation is also very simple.Reduction is carried out in Raney Ni/KBH4/H2O and non-crystalline state Ni/KBH4/H2O reduction system, and directly the product that generates is exactly an amino acid salts, and nickel can recycling.

Angle from reaction, ketoxime acid ester is with Raney Ni-NaBH4 or Raney Ni-KBH4 or non-crystalline state Ni-NaBH4 or non-crystalline state Ni-KBH4 or Al-Ni/NaOH is reduced to the ketoxime acid ester of different structure under alkaline condition or the reduction of ketoxime acid provides effective means, also makes the present invention have using value more widely simultaneously.In different reduction systems, for the convenience of next step fractionation, in the reductive system, add acetic anhydride, directly obtain acetylamino acid.

A kind of still untapped reduction system proposes in the present invention first, and has obtained very good effect in the reduction of carbon nitrogen repeat key, Here it is Raney Ni-NaBH4 or Raney Ni-KBH4 or non-crystalline state Ni-NaBH4 or non-crystalline state Ni-KBH4 reduction system.And non-crystalline state Ni-NaBH4 or non-crystalline state Ni-KBH4 reduction system have lower cost.Here reduction systems that relate to are used for all not appearing in the newspapers as yet amino acid whose synthesizing.

Each method all can be used for synthetic adjacent; right; between halo; alkyl; nitro; amino; hydroxyl; acyl group; carboxyl; the alkylsulfonyl alkoxyl group; acyloxy; alkylamino; amidos etc. are single to be replaced; two replace; three replace N-acetylphenylalanine methyl esters and corresponding acid, also can be used to prepare N-acetonaphthone alanine methyl ester; the thienylalanine methyl esters; the thienylalanine methyl esters; the furans alanine methyl ester; pyrroles's alanine methyl ester; thiazole alanine methyl ester oxazole alanine methyl ester; the pyrazol alanine methyl esters; the Histidine methyl esters; the pyrazoleahtnine methyl esters; the pyrimidine alanine methyl ester; the pyridazine alanine methyl ester; the pyrazine alanine methyl ester; the quinoline alanine methyl ester; the isoquinoline 99.9 alanine methyl ester; aryl alanine ester and corresponding different positions substituent and corresponding amino acid such as indoles alanine methyl ester.Same method also can also be used for R and be other or the N-acetylated fat base amino acid ester that contains functional group or do not contain functional group.

The remarkable advantage that the present invention compared with prior art has: it has synthesis yield height, simple to operate, wide adaptability and characteristics such as the biological fractionation of later stage of being more convenient for.

Description of drawings

Fig. 1 is amino acid whose general structure.

Illustrate: n=0,1,2,3,4......

The R=aralkyl, substituted aralkyl, fatty group, alicyclic radical, aryl, hydrogen.

Embodiment

The present invention is further illustrated below in conjunction with accompanying drawing.

Amino acid involved in the present invention comprises natural amino acid and alpha-non-natural amino acid, and structure is illustrated in figure 1 as amino acid whose general structure.

Wherein, n=0,1,2,3,4......

The R=aralkyl, substituted aralkyl, fatty group, alicyclic radical, aryl, hydrogen

R aryl here and aryl can be isocyclic aryl such as phenyl, naphthyl etc., also comprise fragrant heterocycle such as thiophene, pyridine.Fatty group comprises and contains functional group and be connected with side chain.Comprise heteroatoms in the alicyclic radical or be the pure carbon ring.

With beta-aromatic-α-acetoxime acid esters is that the product that raw material reduction generates is beta-aromatic-α-Bing Ansuan, and other ketoxime acid esters also principle generate corresponding amino acid, its process is basic identical.

The preparation of embodiment 1N-acetyl-2-naphthylalanine

Add naphthalene acetoxime acid 0.05mol in the four-hole boiling flask of being furnished with stirring, thermometer, methyl alcohol 100mL adds the 1.0g amorphous nickel, slowly drips 2.5g NaBH ₄10mL (5mol/L) NaOH solution, keep about 50 ℃ of temperature of reaction.Be added dropwise to complete the back and add 10mL acetic anhydride, stirring at room 2h.With the reaction solution suction filtration, transfer pH to 4 with 2% hydrochloric acid, use ethyl acetate extraction 3 times, anhydrous MgSO ₄Drying, concentrate N-acetonaphthone L-Ala product crude product, 95% ethyl alcohol recrystallization obtains product, yield 92%.

The preparation of embodiment 33-pyrazoleahtnine

Add 3-pyridine acetoxime acid 0.05mol in the four-hole boiling flask of being furnished with stirring, thermometer, methyl alcohol 100mL adds 1.2g Raney Ni, slowly drips 2.3g NaBH ₄10mL (5mol/L) NaOH solution, keep about 45 ℃ of temperature of reaction.With the reaction solution suction filtration, transfer pH to 4 with 2% hydrochloric acid, use ethyl acetate extraction 2 times.Collect the aqueous solution, be evaporated to solid and separated out, crystallisation by cooling, filter thick product.Mother liquor is refining with resin cation (R.C.), obtains other a part of product, yield 84%.If after reduction finishes, directly add diacetyl oxide and can obtain N-acetylize fenclonine, aftertreatment is with example 2.

The preparation of embodiment 4N-acetyl-3-(2-thiophene) L-Ala

0.1mol 2-thiophene acetoxime acid methyl esters is dissolved in the methanol aqueous solution of 100mL50%, adds the 12g alumel, stirs, is heated to 50 ℃, slowly adds the NaOH solution 26mL about 10%, insulation reaction 5h in batches.After TLC can't check raw material, add the acetic anhydride of 0.15mol, reaction 3h.Aftertreatment obtains N-acetyl-3-(2-thiophene) L-Ala, yield 90% with test 2.

Claims (4)

1. the amino acid whose novel method of ketoxime acid ester reduction preparation is characterized in that reduction system is Ni/KBH ₄And Al-Ni/NaOH, described reduction system can be satisfied with the reductive requirement of alkaline condition, and the selection of different reduction systems depends on different synthetic purposes; Described ketoxime acid ester is alpha-ketoxime acid ester and non-alpha-ketoxime acid ester two classes.

2. the amino acid whose novel method of a kind of ketoxime acid ester reduction preparation as claimed in claim 1 is characterized in that the reduction under the described alkaline condition may further comprise the steps:

1. in the reaction flask of being furnished with stirring, thermometer, add ketoxime acid ester and the Ni that is dissolved in methyl alcohol, slowly drip KBH then ₄Methyl alcohol and concentration be 5mol/L NaOH solution, between 25～80 ℃ of the temperature of reaction, ketoxime acid ester and KBH ₄Mol ratio be 1: 0.3～1.5; Methyl alcohol is reaction solvent, and its amount is controlled at 55～80% of reaction volume;

2. by with the ketoxime acid ester mol ratio be that 1: 1～1.05 amount adds acetic anhydride and 1. in the reaction solution, down continues stirring reaction 30min～3h in room temperature condition to above-mentioned steps;

3. reaction solution concentrates, and reclaims methyl alcohol and acetic acid, adds acid in the residuum, and transferring pH is 3.5～5.0, promptly has product N-acetylamino acid to separate out;

Wherein, described Ni is a kind of among non-crystalline state Ni and the Raney Ni.

3. the amino acid whose novel method of a kind of ketoxime acid ester reduction preparation as claimed in claim 2 is characterized in that the reduction under the described alkaline condition can also be following steps:

1. add naphthalene acetoxime acid 0.05mol in the reaction flask of the 250mL that is furnished with stirring, thermometer respectively, methyl alcohol 100mL adds 1.0g Raney Ni, slowly drips 2.5g KBH ₄10mL, the NaOH solution that concentration is counted 5mol/L, keep about 50 ℃ of temperature of reaction;

2. be added dropwise to complete the back and add 10mL acetic anhydride, stirring at room 2h;

3. the suction filtration reaction solution concentrates and reclaims methyl alcohol and acetic acid, adds 2% hydrochloric acid in the residuum and transfers pH to 4, separates out N-acetonaphthone L-Ala crude product, obtains N-acetonaphthone L-Ala product with 95% ethyl alcohol recrystallization.

4. the amino acid whose novel method of a kind of ketoxime acid ester reduction preparation as claimed in claim 1 is characterized in that described ketoxime acid ester comprises methyl esters and ethyl ester, and amino acid comprises a-amino acid, beta-amino acids, gamma-amino acid and δ-amino acid.