CN103265616B - N(2)-L-alanyl-L-glutamine synthesis method - Google Patents

N(2)-L-alanyl-L-glutamine synthesis method Download PDF

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CN103265616B
CN103265616B CN201310169606.3A CN201310169606A CN103265616B CN 103265616 B CN103265616 B CN 103265616B CN 201310169606 A CN201310169606 A CN 201310169606A CN 103265616 B CN103265616 B CN 103265616B
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glutaminate
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ala
gln
glutamine
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CN103265616A (en
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张月忠
赵俊女
张志媛
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BAODING LONGRUI PHARMACEUTICAL TECHNOLOGY Co Ltd
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Abstract

The invention relates to an N(2)-L-alanyl-L-glutamine synthesis method. The method comprises the following steps: reacting an initial raw material L-glutamine with pyruvoyl chloride to obtain alanyl-L-glutamine, reacting alanyl-L-glutamine with hydroxylamine hydrochloride or O-alkylhydroxylamine to obtain N(2)-2'-hydroximino-propionyl-glutamine or N(2)-2'-alkoxyimino-propionyl-glutamine, and hydrogenating to obtain N(2)-L-alanyl-L-glutamine. The method has the advantages of simple operation, mild reaction conditions, stable raw material sources, low cost, safe operation, environmental protection, and wide industrialized application prospect when the method is used for synthesizing N(2)-L-alanyl-L-glutamine.

Description

A kind of synthetic method of N (2)-Ala-Gln
Technical field
The present invention relates to the field of chemical synthesis, in particular to the synthetic method of a kind of compound N (2)-Ala-Gln.
Background technology
L-glutaminate is total free aminoacids the abundantest in human muscle, accounts for 60% of blood Free Amino Acids.L-glutaminate has very important physiological action to human body, it is the energy of the quick somatoblast such as intestinal cells, lymphocyte, scavenger cell, extracellular L-glutaminate concentration can affect lymphocytic differentiation, the generation of cytokine, the germicidal action of macrophage phagocytic and secretion activity and neutrophil leucocyte.Under normal circumstances, L-glutaminate can be synthesized, so be regarded as non-essential amino acid at tissues such as muscle in a large number by L-glutamic acid, α-amino-isovaleric acid, Isoleucine, when human body is in stress situation, such as wound, operation, burn, during infection, L-glutaminate provides nitrogenous source for intestinal epithelial cells and immunocyte, promote protein synthesis, thus cause the concentration of L-glutaminate in blood plasma to decline rapidly, although now L-glutaminate is muscle tissue release, but the demand of organism metabolism can not be met far away, and cause Epithelium of intestinal villus atrophy because of L-glutaminate deficiency in body, intestines wall permeability increases, body's immunity is low, muscle tissue loss etc., therefore L-glutaminate should be supplemented to promote positive nitrogen balance, retain muscle tissue, strengthen immunologic function, keep intestinal mucosa integrity and regulating intestinal canal flora, but the physico-chemical property of L-glutaminate monomer is unstable, especially poisonous Pyrrolidonecarboxylic acid can be formed in heat-processed, therefore the L-glutaminate that the dipeptides containing Gln comes in added body can usually be used clinically.
N (2)-Ala-Gln (CAS:393570-23-0), structure is as follows:
It is the dipeptides that a kind of L-Ala and glutamine condensation are formed, N (2) under the normal temperature-solubleness of Ala-Gln in water very high (568g/L), and stable in properties, under different pH condition, heat sterilization (120 DEG C, 0.5 hour) also can not produce poisonous Pyrrolidonecarboxylic acid and ammonia.Most importantly the pepx that N (2)-Ala-Gln enters after in body in the rapid body of meeting is hydrolyzed to ALANINE and L-glutaminate, effectively can supplement the L-glutaminate of needed by human body.Pharmacokinetics shows, N (2)-Ala-Gln transformation period is in vivo very short, be about 3.8 minutes, a small amount of N (2)-Ala-Gln only can be detected in blood, and only have 1 ~ 2% of intake to get rid of from urine, illustrate that N (2)-Ala-Gln can be utilized by body effectively thus, avoid physiological and pharmacological infringement that N (2)-Ala-Gln causes.N (2)-Ala-Gln is current widely used parenteral nutrient solution clinically.
The synthetic method of N (2)-Ala-Gln mainly contains following several:
1, D-halopropanoic acid and SOCl 2be obtained by reacting halo propionyl chloride, then obtain D-halo propionyl-L-glutaminate with L-glutaminate condensation in the basic conditions, then obtain N (2)-Ala-Gln through ammonolysis reaction, reaction scheme is as follows:
Because D-2-bromo acid price is more expensive, in industrial production, the D-2-of use chloropropionic acid synthesizes N (2)-Ala-Gln more.This is the main method (Organic ProcessResearch and Development2000,4,147-152) of synthesizing N (2)-Ala-Gln at present.But the source of D-2-chloropropionic acid is very restricted, domestic only have several to produce D-2-chloropropionic acid, in what is more important final step ammonolysis reaction, use a large amount of excess of ammonia, thus can cause very serious pollution.
2, first obtain acid anhydrides with L-Ala and phosgene reaction, then with L-glutaminate condensation, decarboxylation obtains N (2)-Ala-Gln (DE3206,784), and reaction scheme is as follows:
Current German Fresenius card adopts this method to produce N (2)-Ala-Gln than company.Because phosgene toxicity is very large, therefore by this route synthesis N (2)-Ala-Gln, require that equipment, personnel and management all will reach higher level, if once misoperation, just may cause very serious consequence.
3, take ALANINE as starting raw material; first by amino tertbutyloxycarbonyl (BOC) or carbobenzoxy-(Cbz) protection; then carboxyl is transformed into active ester; again with L-glutaminate condensation; deprotection obtains final product (CN1295079, WO0039925, US5032675; CN139235, CN1683391).
With this thinking synthesis N (2)-Ala-Gln, operation steps is comparatively loaded down with trivial details, N-hydroxy-succinamide and the DCC of price comparison costliness can be used simultaneously, thus use the producer of this thinking synthesis N (2)-Ala-Gln few both at home and abroad.In addition, some bibliographical informations are also had to cross the synthesis of N (2)-Ala-Gln, but complex operation step, be only applicable to laboratory synthesis, industrialized application prospect is little.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of N (2)-Ala-Gln, the method raw materials enjoy stable sources, with low cost, operational safety simultaneously, environmental friendliness, industrial applications has a extensive future.
To achieve these goals, the present invention takes following technical scheme:
A kind of synthetic method of N (2)-Ala-Gln, comprises the following steps:
A () acetone acyl chlorides (1) and glutamine are obtained by reacting pyruvoyl-L-glutaminate (2):
B oxammonium hydrochloride that () pyruvoyl glutamine (2) and oxammonium hydrochloride or O-alkyl replace is obtained by reacting 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3):
Wherein R can be H, allyl group or benzyl;
C () 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3) obtain N (2)-Ala-Gln (4) through catalytic hydrogenation:
The temperature of this step reaction is 0 ~ 40 DEG C; Catalyzer used is Pd-C, Pd (OH) 2-C, Pd-bauxitic clay, PdCl 2or PdCl 2(PPh 3) 2, the alkali added in reaction is aniline, benzylamine, hexahydroaniline or TERTIARY BUTYL AMINE; Reaction solvent is methyl alcohol, ethanol or Virahol, or their mixtures of being formed with water respectively.
Preferably, in described step (a), react and carry out in the aqueous solution of sodium hydroxide or potassium hydroxide, the pH value 9 ~ 11 of solution, temperature of reaction 0 ~ 10 DEG C, after reacting completely, solution furnishing acidity is separated out product.Preferred further, the pH value 10 of solution, temperature of reaction 0 ~ 5 DEG C, separates out product by hydrochloric acid or sulfuric acid regulation solution pH value 1 ~ 3 after reacting completely.
Preferably, in described step (b), reaction is carried out in alcoholic solution, the oxammonium hydrochloride that described oxammonium hydrochloride or O-alkyl replace is made sodium acetate aqueous solution, aqueous sodium hydroxide solution or alcoholic solution and uses, and with acid, pH value is adjusted to 1 ~ 3 and separates out product after reacting completely.Preferred further, react and carry out in ethanolic soln, the oxammonium hydrochloride that described oxammonium hydrochloride or O-alkyl replace is made sodium acetate aqueous solution or ethanolic soln use, after reacting completely, with acid, pH value is adjusted to 1 precipitation product.
Preferably, in described step (c), the consumption of used catalyst is 1 ~ 5% (mole number) of substrate, and hydrogen pressure used is 1 ~ 5 normal atmosphere, after reacting completely, solution furnishing acidity is separated out product.Preferred further, after reacting completely, regulator solution pH value 4 ~ 6 separates out product.
The committed step of said synthesis route is that oxime or oxime ether are obtained N (2)-Ala-Gln through catalytic hydrogenation.Recent domestic has carried out large quantity research to the catalytic hydrogenation of pyruvic acid oxime, Toratane Munegumi etc. is obtained by reacting pyroracemamide with chiral primary amine and pyruvic acid, then ketone carbonyl is changed into oxime or oxime ether with oxammonium hydrochloride derivatives reaction, optically active L-Ala (Bull.Chem.Soc.Jpn is obtained finally by catalytic hydrogenation, hydrolysis, 61,1425-1427,1988).
From the discussion to reaction result, in the process of catalytic hydrogenation, first the oxygen of acid amides and the nitrogen of oxime form a kind of intermediate of chelating with Pd coordination, and then on amide nitrogen, substituent configuration induces the configuration of last hydrogenated products.In synthetic route of the present invention, when intermediate (3) changes N (2)-Ala-Gln into through catalytic hydrogenation, if add sterically hindered larger alkali, induced synthesis final product has good d.e value.
Beneficial effect of the present invention is:
1, raw materials enjoy stable sources, with low cost.The oxammonium hydrochloride used in synthesis, pyruvic acid and L-glutaminate are conventional synthesis material, and price is very cheap; Simultaneously in the process of catalytic hydrogenation, utilize existing chiral centre to induce generation second chiral centre, expensive chiral ligand need not be added, also greatly reduce cost;
2, synthetic route environmental protection, does not relate to the use of hazardous agents and solvent.The condensation reaction of acetone acyl chlorides and L-glutaminate is carried out in water, and Oximation carries out in ethanol, and final step hydrogenation carries out in water-methanol or water-ethanol.The primary solvent used in reaction is water, methyl alcohol and ethanol, wherein methyl alcohol, and ethanol is recyclable after using to be applied mechanically; The Pd-C used in final step reaction, by filtered and recycled, reuses after activated, not only can reduce costs, also environmental protection.
Embodiment
Embodiment one:
1, the synthesis of pyruvoyl-L-glutaminate
73g (0.5mol) L-glutaminate adds in 500mL water, and 0 DEG C dropwise adds 10%NaOH and adjusts pH to be 10, keeps this temperature, dropwise add 68.9g (0.65mol) acetone acyl chlorides, remain that pH value is about 10 in dropping process.Dropwise, in 0 ~ 5 DEG C of reaction 30min, rise to room temperature and continue reaction 4h, stopped reaction.Under condition of ice bath, dropwise add 2mol/LHCl and adjust pH to 1 ~ 2,0 ~ 5 DEG C of hold over night, has a large amount of white solid to separate out, and filters, and a small amount of frozen water washing, vacuum-drying obtains white crystals 77.8g, yield 74%, m.p.83-85 DEG C. 1H-NMR(CDCl 3)，δ：8.03(s，1H)，7.16(s，2H)，4.56(t，1H)，2.17(s，3H)，2.12(m，2H)，2.05(t，2H)。EI-MS m/z：216。
2, N (2)-2 '-hydroxyl imido grpup-propionyl-L-glutaminate and synthesis
54g (0.25mol) pyruvoyl glutamine is dissolved in 150mL ethanol, the aqueous solution 100mL of 20.9g (0.3mol) oxammonium hydrochloride and 32.8g (0.4mol) sodium-acetate is dropwise added under stirring, dropwise, in stirred at ambient temperature 5h, with the HCl of 5%, pH is adjusted to 1, extract by 3 × 100mL ethyl acetate, extract phase anhydrous Na 2sO 4drying, concentrates to obtain white solid 53g, yield 92%, m.p.94-96 DEG C. 1H-NMR(CDCl 3)，δ：8.05(s，1H)，7.15(s，2H)，4.54(t，1H)，3.12(s，3H)，2.11(m，2H)，2.04(t，2H)。EI-MS m/z：231。
3, the synthesis of N (2)-Ala-Gln
14.8g (0.15mol) hexahydroaniline adds in the hydrogenation reaction cauldron of 300mL methyl alcohol or methanol-water (1: 2) solution, add 23.1g (0.1mol) N (2)-2 '-hydroxyl imido grpup-propionyl-L-glutaminate successively, 5gPd-C (10% charge capacity), passes into N 2, then pass into H 2to 1 normal atmosphere, stir and react 10h in 25 DEG C.React complete, cross and filter Pd-C, filtrate is concentrated into about 50mL, is 6 with second acid for adjusting pH, adds 500mL ethanol, and a large amount of white solid is separated out, and filter, washing with alcohol, vacuum-drying obtains product 20.4g, d.e value 79.4%.Alcohol-water recrystallization obtains N (2)-Ala-Gln 16.5g, yield 76%, d.e > 95%, m.p.214-215 DEG C (decomposition) (document 215-217 DEG C) twice. 1H-NMR(D 2O)，δ：7.35-7.45(m，5H)，4.18(dd，1H)，4.12(s，1H)，2.34(dd，2H)，2.13(m，1H)，1.98(m，1H)，1.56(s，3H)。EI-MS m/z：217。
Embodiment two:
1, the synthesis of pyruvoyl-L-glutaminate
73g (0.5mol) L-glutaminate adds in 600mL water, and 2 DEG C dropwise add 5%KOH and adjust pH to be 11, keep this temperature, dropwise add 0.8mol acetone acyl chlorides, remain that pH value is about 11 in dropping process.Dropwise, in 0 ~ 3 DEG C of reaction 40min, rise to room temperature and continue reaction 5h, stopped reaction.Under condition of ice bath, dropwise add 1mol/LH 2sO 4adjust pH to 2 ~ 3,0 ~ 3 DEG C of hold over night, has a large amount of white solid to separate out, and filters, and a small amount of frozen water washing, vacuum-drying obtains white crystals 77.8g, yield 76%, m.p.83-85 DEG C. 1H-NMR(CDCl 3)，δ：8.03(s，1H)，7.16(s，2H)，4.56(t，1H)，2.17(s，3H)，2.12(m，2H)，2.05(t，2H)。EI-MS m/z：216。
2, the synthesis of N (2)-2 '-benzyloxy imido grpup-propionyl-L-glutaminate
54g (0.25mol) pyruvoyl glutamine is dissolved in 150mL methyl alcohol, adds 36.9g (0.3mol) O-benzyl hydroxylamine ethanolic soln 70mL, react 6h under room temperature under stirring.Solution is concentrated into 80mL by decompression, uses 3%H 2sO 4pH is adjusted to 2, extracts by 3 × 100mL ethyl acetate, extract phase anhydrous Na 2sO 4drying, concentrates to obtain white solid 72.6g, yield 90.5%, m.p.60-62 DEG C. 1H-NMR(CDCl 3)，δ：8.03(s，1H)，7.35-7.45(m，5H)，7.16(s，2H)，4.81(s，2H)，4.55(t，1H)，3.12(s，3H)，2.12(m，2H)，2.04(t，2H)。EI-MS m/z：321。
3, the synthesis of N (2)-Ala-Gln
22g (0.3mol) TERTIARY BUTYL AMINE adds in the hydrogenation reaction cauldron of 300mL ethanol or alcohol-water (1: 2) solution, add 32.1g (0.1mol) N (2)-2 '-benzyloxy imido grpup-propionyl-L-glutaminate successively, 7gPd (OH) 2-C (10% charge capacity), passes into N 2, then pass into H 2to 2 normal atmosphere, stir and react 8h in 40 DEG C.React complete, cross and filter Pd (OH) 2-C, filtrate is concentrated into about 60mL, is 5 with salt acid for adjusting pH, adds 500mL ethanol, and a large amount of white solid is separated out, and filter, washing with alcohol, vacuum-drying obtains product 19.2g, d.e value 76.4%.Alcohol-water recrystallization obtains N (2)-Ala-Gln 13.2g, yield 60.8%, d.e > 95%, m.p.215-216 DEG C (decomposition) (document 215-217 DEG C) twice.
Embodiment three:
1, the synthesis of pyruvoyl-L-glutaminate
73g (0.5mol) L-glutaminate adds in 400mL water, and 1 DEG C dropwise adds 8%NaOH and adjusts pH to be 9, keeps this temperature, dropwise add 1mol acetone acyl chlorides, remain that pH value is about 9 in dropping process.Dropwise, in 5 ~ 10 DEG C of reaction 50min, rise to room temperature and continue reaction 6h, stopped reaction.Under condition of ice bath, dropwise add 3mol/LHCl and adjust pH to 2 ~ 3,5 ~ 10 DEG C of hold over night, have a large amount of white solid to separate out, and filter, and a small amount of frozen water washing, vacuum-drying obtains white crystals 77.8g, yield 72%, m.p.83-85 DEG C. 1H-NMR(CDCl 3)，δ：8.03(s，1H)，7.16(s，2H)，4.56(t，1H)，2.17(s，3H)，2.12(m，2H)，2.05(t，2H)。EI-MS m/z：216。
The synthesis of 2, N (2)-2 '-allyl oxygen imido grpup-propionyl-L-glutaminate
54g (0.25mol) pyruvoyl glutamine is dissolved in 200mL Virahol, adds the aqueous solution 100mL of 32.8g (0.3mol) O-allyl group hydroxylamine hydrochloride and 0.1mol sodium hydroxide under stirring, and in room temperature reaction 5h.PH is adjusted to 3 by the HCl reacting complete use 5%, extracts by 3 × 100mL ethyl acetate, and extract phase anhydrous Na 2SO4 is dry, concentrates to obtain lurid oily liquids 57.3g, yield 84.6%.1H-NMR(CDCl3)，δ：8.03(s，1H)，7.15(s，2H)，6.06(dd，1H)，5.42(dd，1H)，5.28(dd，1H)，4.55(t，1H)，4.2(d，2H)，3.10(s，3H)，2.12(m，2H)，2.02(t，2H)。EI-MS m/z：271。
3, the synthesis of N (2)-Ala-Gln
16g (0.15mol) benzylamine or 0.15mol aniline add in the hydrogenation reaction cauldron of 300mL Virahol or isopropanol-water (1: 2) solution, add 27.1g (0.1mol) N (2)-2 '-allyl oxygen imido grpup-propionyl-L-glutaminate successively, 7g bi triphenyl phosphorus palladium chloride (15% noble metal support amount), passes into N 2, then pass into H 2to 5 normal atmosphere, stir and react 8h in 0 DEG C.React complete, cross and filter bi triphenyl phosphorus palladium chloride, filtrate is concentrated into about 50mL, is 4 with sulfuric acid acid for adjusting pH, adds 500mL ethanol, and a large amount of white solid is separated out, and filter, washing with alcohol, vacuum-drying obtains product 19.6g, d.e value 77.5%.Alcohol-water recrystallization obtains N (2)-Ala-Gln 14.5g, yield 66.8%, d.e > 95%, m.p.215-216 DEG C (decomposition) (document 215-217 DEG C) twice.

Claims (3)

1. a synthetic method for N (2)-Ala-Gln, is characterized in that: comprise the following steps:
A () acetone acyl chlorides (1) and glutamine are obtained by reacting pyruvoyl-L-glutaminate (2):
In step (a), react and carry out in the aqueous solution of sodium hydroxide or potassium hydroxide, the pH value 9 ~ 11 of solution, reacts after carrying out 30 ~ 50 minutes at 0 ~ 10 DEG C and rises to room temperature reaction, after reacting completely, solution furnishing acidity is separated out product;
B oxammonium hydrochloride that () pyruvoyl glutamine (2) and oxammonium hydrochloride or O-alkyl replace is obtained by reacting 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3):
In step (b), R is H, allyl group or benzyl, carries out under room temperature in alcoholic solution, with acid, pH value is adjusted to 1 ~ 3 and separates out product after reacting completely;
C () 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3) obtain N (2)-Ala-Gln (4) through catalytic hydrogenation:
Temperature of reaction in step (c) is 0 ~ 40 DEG C, and catalyzer used is selected from Pd-C, Pd (OH) 2-C, Pd-bauxitic clay, PdCl 2or PdCl 2(PPh 3) 2the consumption of catalyzer calculates into substrate 1 ~ 5% in molar ratio, alkali is added in step (c) reaction, the alkali added is aniline, benzylamine, hexahydroaniline or TERTIARY BUTYL AMINE, reaction solvent is methyl alcohol, ethanol or Virahol, or their mixtures of being formed with water respectively, hydrogen pressure used is 1 ~ 5 normal atmosphere, and after reacting completely, regulator solution pH value 4 ~ 6 separates out product.
2. the synthetic method of N (2)-Ala-Gln as claimed in claim 1, it is characterized in that in described step (a), the pH value 10 of solution, react and rise to room temperature reaction 0 ~ 5 DEG C of reaction after 30 minutes, after reacting completely, separate out product by hydrochloric acid or sulfuric acid regulation solution pH value 1 ~ 2.
3. the synthetic method of N (2)-Ala-Gln as claimed in claim 1 or 2, it is characterized in that in described step (b), reaction is carried out in ethanolic soln, the oxammonium hydrochloride that described oxammonium hydrochloride or O-alkyl replace is made sodium acetate aqueous solution or ethanolic soln use, after reacting completely, with acid, pH value is adjusted to 1 precipitation product.
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