CN103265616A - N(2)-L-alanyl-L-glutamine synthesis method - Google Patents
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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
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)-L-alanyl-L-glutamine.
Background technology
L-glutaminate is total free aminoacids the abundantest among the human muscle, accounts for 60% of total free aminoacids in the blood.L-glutaminate has very important physical effect to human body, it is the energy of somatoblast fast such as intestinal cells, lymphocyte, scavenger cell, extracellular L-glutaminate concentration can influence lymphocytic differentiation, production of cytokines, the germicidal action of macrophage phagocytic and secretion activity and neutrophil leucocyte.Under the normal circumstances, L-glutaminate can be synthesized at tissues such as muscle in a large number by L-glutamic acid, Xie Ansuan, Isoleucine, so be regarded as non-essential amino acid; When human body is in stress situation; wound for example; operation; burn; during infection; L-glutaminate provides nitrogenous source for intestinal epithelial cells and immunocyte; promote protein synthesis; thereby cause that the concentration of L-glutaminate descends rapidly in the blood plasma; though this moment, L-glutaminate discharged for muscle tissue; but can not satisfy the demand of organism metabolism far away; and cause the Epithelium of intestinal villus atrophy because of L-glutaminate deficiency in the body; intestines wall permeability increases; body's immunity is low; muscle tissue loss etc.; therefore should replenish L-glutaminate promotes positive nitrogen balance; keep muscle tissue; raise immunity; keep the intestinal mucosa integrity and regulate intestinal microflora; but the physico-chemical property instability of L-glutaminate monomer; especially can form poisonous Pyrrolidonecarboxylic acid in the heat-processed, therefore can use the dipeptides that contains Gln to come the interior L-glutaminate of added body clinically usually.
N (2)-L-alanyl-L-glutamine (CAS:393570-23-0), structure is as follows:
It is the dipeptides that a kind of L-Ala and glutamine condensation form, N under the normal temperature (the 2)-solubleness of L-alanyl-L-glutamine in water very high (568g/L), and stable in properties, heat sterilization under different pH condition (120 ℃, 0.5 hour) can not produce poisonous Pyrrolidonecarboxylic acid and ammonia yet.The of paramount importance N of being (2)-L-alanyl-L-glutamine can be hydrolyzed to L-L-Ala and L-glutaminate by the pepx in the body rapidly after entering in the body, can replenish the L-glutaminate of needed by human body effectively.Pharmacokinetics shows, N (2)-L-alanyl-L-glutamine transformation period in vivo is very short, be about 3.8 minutes, only can detect minor N (2)-L-alanyl-L-glutamine in the blood, and only have 1~2% of intake from urine, to get rid of, illustrate that thus N (2)-L-alanyl-L-glutamine can be utilized by body effectively, avoided the infringement of the physiological that N (2)-the L-alanyl-L-glutamine causes and pharmacological.N (2)-L-alanyl-L-glutamine is widely used parenteral nutrition liquid clinically at present.
The synthetic method of N (2)-L-alanyl-L-glutamine mainly contains following several:
1, D-halopropanoic acid and SOCl
2Reaction obtains the halo propionyl chloride, obtains D-halo propionyl-L-glutaminate with the L-glutaminate condensation then under alkaline condition, obtains N (2)-L-alanyl-L-glutamine through ammonolysis reaction then, and reaction scheme is as follows:
Because D-2-bromo acid price is more expensive, the synthetic N (2) of the D-2-chloropropionic acid-L-alanyl-L-glutamines that use in the industrial production more.This be the main method of synthesizing N (2)-L-alanyl-L-glutamine at present (Organic Process Research and Development2000,4,147-152).But the source of D-2-chloropropionic acid is very restricted, and domestic have only several families to produce the D-2-chloropropionic acid, in the what is more important final step ammonolysis reaction, use a large amount of excess of ammonias, thereby can cause very serious pollution.
2, at first obtain acid anhydrides with L-Ala and phosgene reaction, again with the L-glutaminate condensation, decarboxylation obtains N (2)-L-alanyl-L-glutamine (DE3206,784), and reaction scheme is as follows:
Present German Fresenius card adopts this method to produce N (2)-L-alanyl-L-glutamine than company.Because phosgene toxicity is very big, therefore by the synthetic N (2) of this route-L-alanyl-L-glutamine, require equipment, personnel and management all will reach higher level, if in case misoperation just may cause very serious consequence.
3, be starting raw material with the L-L-Ala, earlier amino protected with tertbutyloxycarbonyl (BOC) or carbobenzoxy-(Cbz), then carboxyl is transformed into active ester; with the L-glutaminate condensation, deprotection obtains final product (CN1295079, WO0039925 again; US5032675, CN139235, CN1683391).
With the synthetic N (2) of this thinking-L-alanyl-L-glutamine, operation steps is comparatively loaded down with trivial details, can use N-hydroxy-succinamide and the DCC of price comparison costliness simultaneously, thereby it is few to use this thinking to synthesize the producer of N (2)-L-alanyl-L-glutamine both at home and abroad.In addition, also have some bibliographical informations to cross the synthetic of N (2)-L-alanyl-L-glutamine, but complex operation step, it is synthetic to be only applicable to the laboratory, and industrialized application prospect is little.
Summary of the invention
The synthetic method that the purpose of this invention is to provide a kind of N (2)-L-alanyl-L-glutamine, this method raw materials enjoy stable sources, with low cost, the while operational safety, environmental friendliness, industrial applications has a extensive future.
To achieve these goals, the present invention takes following technical scheme:
The synthetic method of a kind of N (2)-L-alanyl-L-glutamine may further comprise the steps:
(a) acetone acyl chlorides (1) obtains pyruvoyl-L-glutaminate (2) with the glutamine reaction:
(b) pyruvoyl glutamine (2) obtains 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3) with the oxammonium hydrochloride reaction that oxammonium hydrochloride or O-alkyl replace:
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)-L-alanyl-L-glutamine (4) through catalytic hydrogenation:
The temperature of this step reaction is 0~40 ℃; Used catalyzer is Pd-C, Pd (OH)
2-C, Pd-bauxitic clay, PdCl
2Or PdCl
2(PPh
3)
2, the alkali that adds in the reaction is aniline, benzylamine, hexahydroaniline or TERTIARY BUTYL AMINE; Reaction solvent is methyl alcohol, ethanol or Virahol, or their mixtures of forming with water respectively.
Preferably, in the described step (a), be reflected in the aqueous solution of sodium hydroxide or potassium hydroxide and carry out, the pH value 9~11 of solution, 0~10 ℃ of temperature of reaction is separated out product with solution furnishing acidity after reacting completely.Further preferred, the pH value 10 of solution, 0~5 ℃ of temperature of reaction, product is separated out with hydrochloric acid or sulfuric acid regulation solution pH value 1~3 in the back that reacts completely.
Preferably, in the described step (b), be reflected in the alcoholic solution and carry out, the oxammonium hydrochloride of described oxammonium hydrochloride or the replacement of O-alkyl is made sodium acetate aqueous solution, aqueous sodium hydroxide solution or alcoholic solution use, the back that reacts completely transfers to 1~3 with acid with the pH value and separates out product.Further preferred, be reflected in the ethanolic soln and carry out, the oxammonium hydrochloride of described oxammonium hydrochloride or the replacement of O-alkyl is made sodium acetate aqueous solution or ethanolic soln use, the back that reacts completely transfers to 1 with acid with the pH value and separates out product.
Preferably, in the described step (c), the consumption of catalyst system therefor is 1~5% (mole number) of substrate, and used hydrogen pressure is 1~5 normal atmosphere, after reacting completely solution furnishing acidity is separated out product.Further preferred, the back regulator solution pH value 4~6 that reacts completely is separated out product.
The committed step of said synthesis route is that oxime or oxime ether are obtained N (2)-L-alanyl-L-glutamine through catalytic hydrogenation.The catalytic hydrogenation of pyruvic acid oxime has been carried out big quantity research both at home and abroad in recent years, usefulness chiral primary amine such as Toratane Munegumi and pyruvic acid reaction obtain pyroracemamide, change the ketone carbonyl into oxime or oxime ether with the oxammonium hydrochloride derivatives reaction then, obtain optically active L-Ala (Bull.Chem.Soc.Jpn finally by catalytic hydrogenation, hydrolysis, 61,1425-1427,1988).
By to the discussion of reaction result as can be known, in the process of catalytic hydrogenation, at first coordination forms a kind of intermediate of chelating with Pd for the oxygen of acid amides and the nitrogen of oxime, and substituent configuration is induced the configuration of last hydrogenated products on the amide nitrogen then.In the synthetic route of the present invention, when intermediate (3) when catalytic hydrogenation changes N (2)-L-alanyl-L-glutamine into, if add sterically hindered bigger alkali, induce to form final product and have good d.e value.
Beneficial effect of the present invention is:
1, raw materials enjoy stable sources, with low cost.The oxammonium hydrochloride that uses in synthetic, pyruvic acid and L-glutaminate are synthesis material commonly used, and price is very cheap; In the process of catalytic hydrogenation, utilize existing chiral centre to induce and produce second chiral centre simultaneously, need not add expensive chiral ligand, also greatly reduced 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, becomes oxime to be reflected in the ethanol and carries out, and the final step hydrogenation carries out in water-methanol or water-ethanol.The primary solvent that uses in the reaction is water, methyl alcohol and ethanol, and methyl alcohol wherein, ethanol use recyclable the applying mechanically in back; The Pd-C that uses in the final step reaction can pass through filtered and recycled, reuses after activated, not only can reduce cost, and environmental protection.
Embodiment
Embodiment one:
1, pyruvoyl-L-glutaminate is synthetic
73g (0.5mol) L-glutaminate adds in the 500mL water, and 0 ℃ dropwise adds 10%NaOH accent pH is 10, keeps this temperature, dropwise adds 68.9g (0.65mol) acetone acyl chlorides, remains the pH value in the dropping process and is about 10.Dropwise, in 0~5 ℃ of reaction 30min, rise to room temperature and continue reaction 4h, stopped reaction.Under the condition of ice bath, dropwise add 2mol/LHCl and transfer pH to 1~2,0~5 ℃ standing over night, have a large amount of white solids to separate out, filter, a small amount of frozen water washing, vacuum-drying gets white crystals 77.8g, yield 74%, m.p.83-85 ℃.
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 synthetic
54g (0.25mol) pyruvoyl glutamine is dissolved in the 150mL ethanol, stir the aqueous solution 100mL that dropwise adds 20.9g (0.3mol) oxammonium hydrochloride and 32.8g (0.4mol) sodium-acetate down, dropwise, under room temperature, stir 5h, HCl with 5% transfers to 1 with pH, with 3 * 100mL ethyl acetate extraction, the extract phase anhydrous Na
2SO
4Drying, concentrate white solid 53g, yield 92%, m.p.94-96 ℃.
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, N (2)-L-alanyl-L-glutamine is synthetic
14.8g (0.15mol) hexahydroaniline adds in the hydrogenation still of 300mL methyl alcohol or methanol-water (1: 2) solution, adds 23.1g (0.1mol) N (2)-2 '-hydroxyl imido grpup-propionyl-L-glutaminate successively, 5gPd-C (10% charge capacity) feeds N
2, feed H then
2To 1 normal atmosphere, stir and in 25 ℃ of reaction 10h.Reaction finishes, and removes by filter Pd-C, and filtrate is concentrated into about 50mL, and regulating pH with acetic acid is 6, adds 500mL ethanol, and a large amount of white solids are separated out, filter, and washing with alcohol, vacuum-drying gets product 20.4g, d.e value 79.4%.The alcohol-water recrystallization gets N (2)-L-alanyl-L-glutamine 16.5g, yield 76%, d.e>95%, m.p.214-215 ℃ (decomposition) (document 215-217 ℃) 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, pyruvoyl-L-glutaminate is synthetic
73g (0.5mol) L-glutaminate adds in the 600mL water, and 2 ℃ dropwise add 5%KOH accent pH is 11, keeps this temperature, dropwise adds 0.8mol acetone acyl chlorides, remains the pH value in the dropping process and is about 11.Dropwise, in 0~3 ℃ of reaction 40min, rise to room temperature and continue reaction 5h, stopped reaction.Under the condition of ice bath, dropwise add 1mol/LH
2SO
4Transfer pH to 2~3,0~3 ℃ standing over night, have a large amount of white solids to separate out, filter, a small amount of frozen water washing, vacuum-drying gets white crystals 77.8g, yield 76%, m.p.83-85 ℃.
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 '-benzyloxy imido grpup-propionyl-L-glutaminate is synthetic
54g (0.25mol) pyruvoyl glutamine is dissolved in the 150mL methyl alcohol, stirs to add 36.9g (0.3mol) O-benzyl hydroxylamine ethanolic soln 70mL down, reacts 6h under the room temperature.Decompression to 80mL, is used 3%H with solution concentration
2SO
4PH is transferred to 2, with 3 * 100mL ethyl acetate extraction, the extract phase anhydrous Na
2SO
4Drying, concentrate white solid 72.6g, yield 90.5%, m.p.60-62 ℃.
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, N (2)-L-alanyl-L-glutamine is synthetic
22g (0.3mol) TERTIARY BUTYL AMINE adds in the hydrogenation still of 300mL ethanol or alcohol-water (1: 2) solution, adds 32.1g (0.1mol) N (2)-2 '-benzyloxy imido grpup-propionyl-L-glutaminate successively, 7gPd (OH)
2-C (10% charge capacity) feeds N
2, feed H then
2To 2 normal atmosphere, stir and in 40 ℃ of reaction 8h.Reaction finishes, and removes by filter Pd (OH)
2-C, filtrate is concentrated into about 60mL, and regulating pH with hydrochloric acid is 5, adds 500mL ethanol, and a large amount of white solids are separated out, filter, washing with alcohol, vacuum-drying gets product 19.2g, d.e value 76.4%.The alcohol-water recrystallization gets N (2)-L-alanyl-L-glutamine 13.2g, yield 60.8%, d.e>95%, m.p.215-216 ℃ (decomposition) (document 215-217 ℃) twice.
Embodiment three:
1, pyruvoyl-L-glutaminate is synthetic
73g (0.5mol) L-glutaminate adds in the 400mL water, and 1 ℃ dropwise adds 8%NaOH accent pH is 9, keeps this temperature, dropwise adds 1mol acetone acyl chlorides, remains the pH value in the dropping process and is about 9.Dropwise, in 5~10 ℃ of reaction 50min, rise to room temperature and continue reaction 6h, stopped reaction.Under the condition of ice bath, dropwise add 3mol/LHCl and transfer pH to 2~3,5~10 ℃ standing over night, have a large amount of white solids to separate out, filter, a small amount of frozen water washing, vacuum-drying gets white crystals 77.8g, yield 72%, m.p.83-85 ℃.
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 '-allyl oxygen imido grpup-propionyl-L-glutaminate is synthetic
54g (0.25mol) pyruvoyl glutamine is dissolved in the 200mL Virahol, stirs the aqueous solution 100mL that adds 32.8g (0.3mol) O-allyl group hydroxylamine hydrochloride and 0.1mol sodium hydroxide down, and in room temperature reaction 5h.Reaction finishes and with 5% HCl pH is transferred to 3, with 3 * 100mL ethyl acetate extraction, and extract phase anhydrous Na 2SO4 drying, concentrated 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, N (2)-L-alanyl-L-glutamine is synthetic
16g (0.15mol) benzylamine or 0.15mol aniline add in the hydrogenation still of 300mL Virahol or Virahol-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) feeds N
2, feed H then
2To 5 normal atmosphere, stir and in 0 ℃ of reaction 8h.Reaction finishes, and removes by filter bi triphenyl phosphorus palladium chloride, and filtrate is concentrated into about 50mL, is 4 with the sulfuric acid acid for adjusting pH, adds 500mL ethanol, and a large amount of white solids are separated out, filter, and washing with alcohol, vacuum-drying gets product 19.6g, d.e value 77.5%.The alcohol-water recrystallization gets N (2)-L-alanyl-L-glutamine 14.5g, yield 66.8%, d.e>95%, m.p.215-216 ℃ (decomposition) (document 215-217 ℃) twice.
Claims (10)
1. the synthetic method of a N (2)-L-alanyl-L-glutamine is characterized in that: may further comprise the steps:
(a) acetone acyl chlorides (1) obtains pyruvoyl-L-glutaminate (2) with the glutamine reaction:
(b) pyruvoyl glutamine (2) obtains 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3) with the oxammonium hydrochloride reaction that oxammonium hydrochloride or O-alkyl replace:
Wherein R is H, allyl group or benzyl;
(c) 2 '-hydroxyl imido grpup propionyl-L-glutaminate or 2 '-alkoxyimino propionyl-L-glutaminate (3) obtain N (2)-L-alanyl-L-glutamine (4) through catalytic hydrogenation:
The temperature of this step reaction is 0~40 ℃;
The catalyzer that reacts used is Pd-C, Pd (OH)
2-C, Pd-bauxitic clay, PdCl
2Or PdCl
2(PPh
3)
2
The alkali that adds in the reaction is aniline, benzylamine, hexahydroaniline or TERTIARY BUTYL AMINE;
Reaction solvent is the mixture that methyl alcohol, ethanol or Virahol or they form with water respectively.
2. the synthetic method of N as claimed in claim 1 (2)-L-alanyl-L-glutamine, it is characterized in that: in the described step (a), be reflected in the aqueous solution of sodium hydroxide or potassium hydroxide and carry out, the pH value 9~11 of solution, 0~10 ℃ of temperature of reaction is separated out product with solution furnishing acidity after reacting completely.
3. the synthetic method of N as claimed in claim 2 (2)-L-alanyl-L-glutamine is characterized in that: in the described step (a), and the pH value 10 of solution, 0~5 ℃ of temperature of reaction, product is separated out with hydrochloric acid or sulfuric acid regulation solution pH value 1~3 in the back that reacts completely.
4. as the synthetic method of claim 1 or 2 or 3 described N (2)-L-alanyl-L-glutamines, it is characterized in that: in the described step (b), be reflected in the alcoholic solution and carry out, the oxammonium hydrochloride of described oxammonium hydrochloride or the replacement of O-alkyl is made sodium acetate aqueous solution, aqueous sodium hydroxide solution or alcoholic solution use, the back that reacts completely transfers to 1~3 with acid with the pH value and separates out product.
5. the synthetic method of N as claimed in claim 4 (2)-L-alanyl-L-glutamine, it is characterized in that: in the described step (b), be reflected in the ethanolic soln and carry out, the oxammonium hydrochloride of described oxammonium hydrochloride or the replacement of O-alkyl is made sodium acetate aqueous solution or ethanolic soln use, and the back that reacts completely transfers to 1 with acid with the pH value and separates out product.
6. the synthetic method of N as claimed in claim 4 (2)-L-alanyl-L-glutamine, it is characterized in that: in the described step (c), the consumption of catalyst system therefor is calculated as 1~5% of substrate in molar ratio, and used hydrogen pressure is 1~5 normal atmosphere.
7. the synthetic method of N as claimed in claim 6 (2)-L-alanyl-L-glutamine is characterized in that: in the described step (c), the back regulator solution pH value 4~6 that reacts completely is separated out product.
8. as the synthetic method of claim 1 or 2 or 3 described N (2)-L-alanyl-L-glutamines, it is characterized in that: in the described step (c), the consumption of catalyst system therefor is calculated as 1~5% of substrate in molar ratio, and used hydrogen pressure is 1~5 normal atmosphere.
9. the synthetic method of N as claimed in claim 8 (2)-L-alanyl-L-glutamine is characterized in that: in the described step (c), the back regulator solution pH value 4~6 that reacts completely is separated out product.
10. the synthetic method of N as claimed in claim 5 (2)-L-alanyl-L-glutamine, it is characterized in that: in the described step (c), the consumption of catalyst system therefor is calculated as 1~5% of substrate in molar ratio, and used hydrogen pressure is 1~5 normal atmosphere; The back regulator solution pH value 4~6 that reacts completely is separated out product.
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CN110372559A (en) * | 2014-12-29 | 2019-10-25 | 重庆博腾制药科技股份有限公司 | One kind (4S)-N-Boc-4-- methoxy-L-PROLINE synthetic method |
WO2018199146A1 (en) * | 2017-04-25 | 2018-11-01 | 学校法人中部大学 | Ester to amide conversion catalyst using oxime-hydroxyamine as substrate |
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