CN109608421A - A kind of synthetic method of 5-aminoketoglutarate hydrochloride - Google Patents
A kind of synthetic method of 5-aminoketoglutarate hydrochloride Download PDFInfo
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- CN109608421A CN109608421A CN201910059999.XA CN201910059999A CN109608421A CN 109608421 A CN109608421 A CN 109608421A CN 201910059999 A CN201910059999 A CN 201910059999A CN 109608421 A CN109608421 A CN 109608421A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
Abstract
The present invention relates to the synthetic methods of 5-aminoketoglutarate hydrochloride (5-ALA) a kind of, with chaff amine (2- furylamine) for starting material, through amido protecting, oxidation reaction, reduction reaction, 4 step of hydrolysis decarboxylation reaction synthesis target product.The reagent price that synthetic method of the present invention uses is cheap to be easy to get, and environmental-friendly, operation is simple.
Description
Technical field
The present invention relates to field of medicinal chemistry, in particular to a kind of synthetic method of 5-aminoketoglutarate hydrochloride.
Background technique
5-ALA (5-ALA) widely exists in animal, plant and microbial cell, is that biosynthesis leaf is green
The precursor substance of the tetrapyrroles such as element, ferroheme, porphyrin and vitamin B12.Since 5-ALA is to people and animals' nontoxicity, in ring
Degradable in border, noresidue plays an important role in life process as organism endogenous material.
5-ALA serves many purposes.In medicine, 5-ALA can be used as photodynamics of the second generation photosensitizer for cancer
Treatment；In clinical research, ALA is in treatment cutaneum carcinoma, colon cancer, lung cancer, carcinoma of mouth, bladder cancer, cancer of the esophagus, oophoroma, cream
The effect of gland cancer, the cancer of the brain etc. is gradually affirmed；In addition, ALA is significant to the therapeutic effect of multidrug resistance cancer cell, it is clinical resistance to
Effective means of supplementing out economy of medicine tumour cell treatment, on June 6th, 2017, FDA had approved its application in glioma treatment
(drug name: Gleolan), the same year, Japan also had approved the product；In terms of cosmetics, ALA can treat respectively as photosensitizer
The refractory diseases such as kind acne, intractable acne, the cutin accumulation of cortex hypersecretion, removal sebum.Agriculturally, ALA can
Growth to promote crop, vegetables and fruit as plant growth regulator, improves the quality of fruit, increases yield.In micro- life
In terms of object culture, the ALA of high concentration can be used as growth inhibitor, for solving the problems, such as that river algae is spread unchecked.
5-ALA has wide application and the prospect of marketing, causes the extensive concern of domestic and foreign scholars and industry.Though
The problems such as structure is simple, but synthesis technology has many disadvantages at present, causes current expensive and environmental pollution, greatly
It is limited greatly in the application in many fields.Domestic and international scientist's research reports many synthetic routes, but these synthetic methods
It mostly has the following deficiencies: that (1) reaction selectivity is poor, causes gross production rate low；(2) severe reaction conditions are not easy to control, and increase
Production cost；(3) raw materials used expensive, production cost is higher.
Summary of the invention
The present invention provides a kind of raw material is simple and easy to get, synthesis step is short, preparation 5- ammonia easy to operate and environmental-friendly
The method of base ketone valerate hydrochlorate (5-ALA).
Purpose to realize the present invention, the invention adopts the following technical scheme:
Reaction route of the invention is as follows:
A kind of synthetic method of 5-aminoketoglutarate hydrochloride, comprising the following steps:
The protection of step (1) amino: in organic solvent, sequentially adding chaff amine (I), alkali and protect reagent, and reaction 0.5~
4h is washed after reaction, is concentrated to give product (II)；Reaction process is expressed as follows:
Wherein R is acetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzoyl, p-toluenesulfonyl, trifluoroacetyl group, neighbour
Phenyl-diformyl base, Fmoc-, benzyl.Preferably benzyloxycarbonyl group, tertbutyloxycarbonyl, acetyl group.
In step (1), the chaff amine (I) is 2- furylamine.
In step (1), the organic solvent is methylene chloride, chloroform, tetrahydrofuran, toluene, acetonitrile, N, N- dimethyl methyl
Amide, dimethyl sulfoxide.Preferably, the organic solvent is chloroform, methylene chloride.
Protection reagent described in step (1) is chloroacetic chloride, (Boc) 2O, Cbz-Cl, acetic anhydride, chlorobenzoyl chloride, to toluene
Sulfonic acid chloride, trifluoro-acetyl chloride, o-phthaloyl chloride, Fmoc-Cl, benzyl bromine.
Alkali described in step (1) is that triethylamine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide, carbonic acid is added
Sodium, potassium carbonate, nano-calcium carbonate potassium；It is preferred that alkali is triethylamine, diisopropyl ethyl amine, potassium carbonate, nano-calcium carbonate potassium.
Reaction temperature described in step (1) is -20~20 DEG C, preferably ice bath (0 DEG C).
Step (2) oxidation reaction: being dissolved in organic solvent for the product that step (1) obtains, buffer and oxidant be added ,-
It is reacted at 10~10 DEG C, obtains oxidation product (III), reaction process is expressed as follows:
Oxidant described in step (2) be selected from sodium hypochlorite, sodium chlorite, sodium chlorate, sodium perchlorate, chlorine dioxide,
One of sodium hypobromite, chlorine, bromine water；It is preferred that chlorine dioxide, sodium hypochlorite, one of sodium chlorite, chlorine.
Buffer described in step (2) is sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride.Preferred oxidant is phosphorus
Acid dihydride sodium, potassium dihydrogen phosphate.
Solvent described in step (2) is selected from methanol, ethyl alcohol, the tert-butyl alcohol, n-butanol, octanol, water and methanol/water, second
One kind of the mixed solvents such as alcohol/water, butanol/water, n-butanol/water, octanol/water, preferably methanol/water, ethanol/water, the tert-butyl alcohol/
The volume ratio of the mixed solvents such as water, n-butanol/water, alcohol and water is alcohol: water=(4~6): 1, preferably alcohol: water=5:1.
It in step (2), is reacted at described -10~10 DEG C, preferably 0 DEG C reaction 3h.
Step (3) reduction reaction: oxidation product (III) is poured into reaction vessel, organic acid or inorganic acid is added, 100
Go back original reagent is slowly added portionwise under~115 DEG C of stirrings, carries out reduction reaction, is filtered after fully reacting, solvent is concentrated under reduced pressure and obtains
Reduzate (IV), reaction process is expressed as follows:
Organic acid described in step (3) is formic acid, acetic acid；Inorganic acid is hydrochloric acid, hydrobromic acid.
If go back original reagent described in step (3) is selected from Zn, Fe, H2/Pd, H2/Pd-C, H2/ activity using organic acid
One of Ni, H2/ Raney's nickel, preferably one of Zn, Fe, H2/Pd-C.If using inorganic acid, described in step (3) also
Original reagent is selected from one of Zn, Fe, H2/ activity Ni, H2/ Raney's nickel, preferably Zn, Fe.
Reaction time described in step (3) is 1~3h, preferably 1.5h.
Step (4) hydrolysis decarboxylation: reduzate (IV) is heated to hydrolysis decarboxylation reaction in aqueous hydrochloric acid solution, is concentrated, again
Crystallization obtains 5-aminoketoglutarate hydrochloride (5-ALA), and reaction process is expressed as follows:
Concentration of hydrochloric acid described in step (4) is 4~8N, preferred concentration 6N.
The molar ratio of hydrochloric acid described in step (4) and reduzate (IV) are (10~12): 1.
Reaction temperature described in step (4) is 100~115 DEG C.
Reaction time described in step (4) is 1~3h, and the preferably time is 1.5h.
The present invention compared with the existing technology the utility model has the advantages that
1, the present invention relates to amido protecting, oxidation, hydro-reduction, hydrolysis decarboxylation four-step reaction, process route is short, environment friend
Good, post-processing is simple, high income.
2, the present invention does not use expensive metal reagent, and easy to operate, raw material is easy to get.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated.
Embodiment 1
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous methylene chloride and 12.5ml chaff amine is added.Ice
Bath (0 DEG C) be added with stirring 26.5ml triethylamine, after 14.15ml chloroacetic chloride is slowly added dropwise.0.5h is reacted under ice bath (0 DEG C).TLC
Detect fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry, take out
Filter obtains thick yellow liquid (II) after concentration.Yield is 95%.
Step (2) oxidation reaction: by the product (II) that step (1) obtains be placed in 500ml flask be added 200ml methanol and
40ml distilled water；(0 DEG C) of ice bath stirring, is once added 19.05g sodium dihydrogen phosphate and 32.92g after solvent temperature drops to 0 DEG C
Sodium hypochlorite.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, under water layer and salt
It is heavy, upper layer methanol solution is collected, suction filtered through kieselguhr is then used, filtrate concentration obtains oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml formic acid, heating is added
To 100 DEG C, 69g zinc powder is added under stirring in batches.100 DEG C of reactions 1h, TLC detect fully reacting.It filters, solvent is concentrated under reduced pressure
It obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: reduzate (IV) is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 115 DEG C of reflux 1h, TLC and detects fully reacting.Concentrated solvent recrystallizes finally with ethanol/methylene
Product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 2
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous methylene chloride and 12.5ml chaff amine is added.Ice
Bath (0 DEG C) be added with stirring doubling dose potassium carbonate, after 27.33ml Cbz-Cl is slowly added dropwise.0.5h is reacted under ice bath (0 DEG C).
TLC detects fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry
It is dry, it filters, obtains thick yellow liquid (II) after concentration.Yield is 94%.
Step (2) oxidation reaction: the product (II) that step (1) obtains is placed in the addition 200ml tert-butyl alcohol in 500ml flask
With 40ml distilled water；(0 DEG C) of ice bath stirring, be once added after solvent temperature drops to 0 DEG C 19.05g sodium dihydrogen phosphate and
32.92g sodium chlorite.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, water layer
Sink with salt, collect upper layer t-butanol solution, then use suction filtered through kieselguhr, filtrate is concentrated to give oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml concentrated hydrochloric acid is added, adds
69g iron powder is added to 100 DEG C in heat in batches under stirring.100 DEG C of reactions 1h, TLC detect fully reacting.It filters, is concentrated under reduced pressure molten
Agent obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: above-mentioned reaction product is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 115 DEG C of reflux 1h, TLC and detects fully reacting.Concentrated solvent recrystallizes finally with ethanol/methylene
Product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 3
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous chloroform and 12.5ml chaff amine is added.Ice bath (0
DEG C) be added with stirring 26.5ml diisopropyl ethyl amine, after 27.33ml (Boc) 2O is slowly added dropwise.0.5h is reacted under ice bath.TLC
Detect fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry, take out
Filter obtains thick yellow liquid (II) after concentration.Yield is 94%.
Step (2) oxidation reaction: by the product (II) that step (1) obtains be placed in 500ml flask be added 200ml ethyl alcohol and
40ml distilled water；(0 DEG C) of ice bath stirring, 19.05g potassium dihydrogen phosphate is once added after solvent temperature drops to 0 DEG C and is passed through foot
Measure chlorine.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, water layer and salt sink,
Upper layer ethanol solution is collected, suction filtered through kieselguhr is then used, filtrate concentration obtains oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml glacial acetic acid is added, adds
Heat stirs lower hydrogen environment and 10%Pd/C 1g is added next time to 100 DEG C.100 DEG C of reactions 1h, TLC detect fully reacting.It takes out
Filter is concentrated under reduced pressure solvent and obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: above-mentioned reaction product is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 115 DEG C of reflux 1h, TLC and detects fully reacting.Concentrated solvent recrystallizes finally with ethanol/methylene
Product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 4
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous methylene chloride and 12.5ml chaff amine is added.Ice
Bath (0 DEG C) be added with stirring doubling dose nano-calcium carbonate potassium, after 27.33ml Fmoc-Cl is slowly added dropwise.It is reacted under ice bath (0 DEG C)
0.5h.TLC detects fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous slufuric acid of organic addition
Sodium is dry, filters, and obtains thick yellow liquid (II) after concentration.Yield is 94%.
Step (2) oxidation reaction: the product (II) that step (1) obtains is placed in addition 200ml n-butanol in 500ml flask
With 40ml distilled water；(0 DEG C) of ice bath stirring；19.05g sodium dihydrogen phosphate and enough is once added after solvent temperature drops to 0 DEG C
Chlorine dioxide；0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, under water layer and salt
It is heavy, upper layer butanol solution is collected, suction filtered through kieselguhr, filtrate concentration are then used.It obtains oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and the second of 150ml hydrogen bromide is added
Acid solution is heated to 100 DEG C, under atmosphere of hydrogen, primary that 2g Raney's nickel is added.100 DEG C of reactions 1h, TLC detect fully reacting.It takes out
Filter is concentrated under reduced pressure solvent and obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: reduzate (IV) is moved in 250ml round-bottomed flask, and the hydrochloric acid 160ml of 6N is added,
It is heated to 115 DEG C of reflux 1h, TLC and detects fully reacting.Concentrated solvent recrystallizes to obtain final product 5- with ethanol/methylene
Aminovaleric acid hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 5
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous methylene chloride and 12.5ml chaff amine is added.Ice
Bath (0 DEG C) be added with stirring 26.5ml triethylamine, after 14.15ml chloroacetic chloride is slowly added dropwise.4h is reacted at -20 DEG C.TLC detection is anti-
It should be complete.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry, filter, it is dense
Thick yellow liquid (II) is obtained after contracting.Yield is 94%.
Step (2) oxidation reaction: by the product (II) that step (1) obtains be placed in 500ml flask be added 200ml methanol and
50ml distilled water；(0 DEG C) of ice bath stirring, is once added 19.05g sodium dihydrogen phosphate and 32.92g after solvent temperature drops to 0 DEG C
Sodium hypochlorite.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, under water layer and salt
It is heavy, upper layer methanol solution is collected, suction filtered through kieselguhr is then used, filtrate concentration obtains oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml formic acid, heating is added
To 115 DEG C, 69g zinc powder is added under stirring in batches.115 DEG C of reactions 1h, TLC detect fully reacting.It filters, solvent is concentrated under reduced pressure
It obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: reduzate (IV) is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 100 DEG C of reflux 3h, TLC and detects fully reacting.Concentrated solvent recrystallizes finally with ethanol/methylene
Product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 6
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous methylene chloride and 12.5ml chaff amine is added.Ice
Bath (0 DEG C) be added with stirring doubling dose potassium carbonate, after 27.33ml Cbz-Cl is slowly added dropwise.0.5h is reacted under ice bath (0 DEG C).
TLC detects fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry
It is dry, it filters, obtains thick yellow liquid (II) after concentration.Yield is 94%.
Step (2) oxidation reaction: the product (II) that step (1) obtains is placed in the addition 200ml tert-butyl alcohol in 500ml flask
With 34ml distilled water；(0 DEG C) of ice bath stirring, be once added after solvent temperature drops to 0 DEG C 19.05g sodium dihydrogen phosphate and
32.92g sodium chlorite.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, water layer
Sink with salt, collect upper layer t-butanol solution, then use suction filtered through kieselguhr, filtrate is concentrated to give oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml concentrated hydrochloric acid is added, adds
69g iron powder is added to 100 DEG C in heat in batches under stirring.100 DEG C of reactions 1.5h, TLC detect fully reacting.It filters, is concentrated under reduced pressure
Solvent obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: above-mentioned reaction product is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 115 DEG C of reflux 1.5h, TLC and detects fully reacting.Concentrated solvent recrystallizes most with ethanol/methylene
Final product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
Embodiment 7
The protection of step (1) amino: take 500ml round-bottomed flask that 250ml anhydrous chloroform and 12.5ml chaff amine is added.Ice bath (0
DEG C) be added with stirring 26.5ml diisopropyl ethyl amine, after 27.33ml (Boc) 2O is slowly added dropwise.0.5h is reacted under ice bath.TLC
Detect fully reacting.It is washed 1 time after being washed with water 3 times with saturated sodium chloride solution, takes the appropriate anhydrous sodium sulfate of organic addition dry, take out
Filter obtains thick yellow liquid (II) after concentration.Yield is 94%.
Step (2) oxidation reaction: by the product (II) that step (1) obtains be placed in 500ml flask be added 200ml ethyl alcohol and
45ml distilled water；(0 DEG C) of ice bath stirring, 19.05g potassium dihydrogen phosphate is once added after solvent temperature drops to 0 DEG C and is passed through foot
Measure chlorine.0 DEG C of reaction 3h.TLC detects fully reacting.Reaction solution is moved on into stratification in separatory funnel, water layer and salt sink,
Upper layer ethanol solution is collected, suction filtered through kieselguhr is then used, filtrate concentration obtains oxidation product (III).
Step (3) reduction reaction: oxidation product (III) is moved in 250ml round-bottomed flask, and 150ml glacial acetic acid is added, adds
Heat stirs lower hydrogen environment and 10%Pd/C 1g is added next time to 100 DEG C.100 DEG C of reactions 3h, TLC detect fully reacting.It takes out
Filter is concentrated under reduced pressure solvent and obtains reduzate (IV).
Step (4) hydrolysis decarboxylation: above-mentioned reaction product is moved in 250ml round-bottomed flask, the hydrochloric acid solution of 6N is added
160ml is heated to 115 DEG C of reflux 1h, TLC and detects fully reacting.Concentrated solvent recrystallizes finally with ethanol/methylene
Product 5-aminoketoglutarate hydrochloride (5-ALA).
Fusing point: 147-148 DEG C.NMR (500M CD3OD) δ: 2.66, (2H, t ,-CH2-), 2.79 (2H, t ,-CH2-),
4.02 (2H, s ,-CH2N-).
The present invention mutually has the advantage that (1) the present invention relates to amido protecting, oxidation, hydro-reduction, four steps of hydrolysis decarboxylation
Reaction, process route is short, environmental-friendly, and post-processing is simple, high income.(2) present invention does not use expensive metal reagent, operation letter
Single, raw material is easy to get.
Claims (10)
1. a kind of synthetic method of 5-aminoketoglutarate hydrochloride, which comprises the following steps:
The protection of step (1) amino: in organic solvent, sequentially adding chaff amine (I), alkali and protection reagent, react 0.5~4h,
After reaction, it washes, be concentrated to give product (II)；Reaction process is expressed as follows:
Wherein R is acetyl group, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzoyl, p-toluenesulfonyl, trifluoroacetyl group, adjacent benzene two
Formoxyl, Fmoc-, one of benzyl；
The alkali is triethylamine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, nano-calcium carbonate potassium
One of；
The organic solvent is methylene chloride, chloroform, tetrahydrofuran, toluene, acetonitrile, n,N-Dimethylformamide, dimethyl Asia
One of sulfone；
Step (2) oxidation reaction: the product that step (1) obtains is dissolved in organic solvent, buffer and oxidant is added, in temperature
A period of time is reacted at -20~20 DEG C of degree, obtains oxidation product (III), reaction process is expressed as follows:
The oxidant is sodium chlorate, sodium chlorite, sodium chlorate, sodium perchlorate, chlorine dioxide, sodium hypobromite, chlorine, bromine water
One of；
Buffer is one of sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride；
The solvent is one of methanol, ethyl alcohol, the tert-butyl alcohol, n-butanol, octanol or the mixed solvent of itself and water；
Step (3) reduction reaction: oxidation product (III) is poured into reaction vessel, and organic acid or inorganic acid is added, 100~
Go back original reagent is slowly added portionwise under 115 DEG C of stirrings, carries out reduction reaction, is filtered after fully reacting, solvent, which is concentrated under reduced pressure, to be gone back
It originates in object (IV), reaction process is expressed as follows:
The organic acid is formic acid, acetic acid；Inorganic acid is one of hydrochloric acid, hydrobromic acid；
Step (4) hydrolysis decarboxylation: reduzate (IV) is heated to hydrolysis decarboxylation reaction, concentration, recrystallization in aqueous hydrochloric acid solution
5-aminoketoglutarate hydrochloride (5-ALA) is obtained, reaction process is expressed as follows:
The reaction temperature is 100~115 DEG C；
The concentration of hydrochloric acid is 4~8N；
The reaction time is 1~3h.
2. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (1),
The R is one of benzyloxycarbonyl group, tertbutyloxycarbonyl, acetyl group；
The alkali is one of triethylamine, diisopropyl ethyl amine, potassium carbonate, nano-calcium carbonate potassium；
The organic solvent is chloroform or methylene chloride；
The protection reagent is chloroacetic chloride, (Boc) 2O, Cbz-Cl, acetic anhydride, chlorobenzoyl chloride, paratoluensulfonyl chloride, trifluoroacetyl
Chlorine, o-phthaloyl chloride, Fmoc-Cl, one of benzyl bromine；Reaction temperature is -20~20 DEG C.
3. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (1),
The alkali be one of triethylamine, diisopropyl ethyl amine, potassium carbonate, nano-calcium carbonate potassium, the reaction temperature be -20~
20℃。
4. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (2),
The oxidant is chlorine dioxide, sodium hypochlorite, one of sodium chlorite, chlorine；The buffer be sodium dihydrogen phosphate or
Potassium dihydrogen phosphate；
The reaction temperature is -10~10 DEG C.
5. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (2),
The solvent is the mixed solvent of one of methanol, ethyl alcohol, the tert-butyl alcohol, n-butanol and water, and the volume ratio of alcohol and water is alcohol:
Water=(4~6): 1.
6. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (3),
If using organic acid, the go back original reagent be one of Zn, Fe, H2/Pd, H2/Pd-C, H2/ activity Ni, H2/ Raney's nickel,
If the go back original reagent is selected from one of Zn, Fe, H2/ activity Ni, H2/ Raney's nickel using inorganic acid；
The reaction time is 1~3h.
7. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (3),
If the go back original reagent is one of Zn, Fe, H2/Pd-C using organic acid；If using inorganic acid, the reduction examination
Agent is Zn or Fe；
The reaction time is 1.5h.
8. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (4),
The molar ratio of the hydrochloric acid and reduzate (IV) is (10~12): 1.
9. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that in step (4),
The concentration of hydrochloric acid is 6N.
10. a kind of synthetic method of 5-aminoketoglutarate hydrochloride as described in claim 1, which is characterized in that including following
Specific steps:
Step (1) amido protecting:
Anhydrous methylene chloride and chaff amine (I), ice bath (0 DEG C) are added in container one and is added with stirring triethylamine, after be slowly added dropwise
Chloroacetic chloride reacts 0.5h at -10~10 DEG C；After TLC detects fully reacting, it is washed with water 3 times, then uses saturated sodium chloride solution
It washes 1 time, takes the appropriate anhydrous sodium sulfate of organic addition dry, filter, obtain thick yellow liquid product (II) after concentration；
The anhydrous methylene chloride, chaff amine (I) and triethylamine volume ratio are as follows: 20:1:2.12
Step (2) oxidation reaction
The product (II) that step (1) obtains is placed in container two, methanol and distilled water is added；(0 DEG C) of ice bath stirring, to solvent
Temperature, which drops to, is once added 19.05g sodium dihydrogen phosphate and 32.92g sodium hypochlorite after 0 DEG C, in 0 DEG C of reaction 3h, TLC detection reaction
After completely, reaction solution is moved on into stratification in separatory funnel, water layer and salt sink, collects upper layer methanol solution, then use silicon
Diatomaceous earth filters, and filtrate concentration obtains oxidation product (III)；
The volume ratio of the methanol and distilled water is alcohol: the mass ratio of water=5:1, the sodium dihydrogen phosphate and sodium hypochlorite is
1.73:1
Step (3) reduction reaction:
Oxidation product (III) is moved in container three, 150mL formic acid is added, is heated to 100 DEG C, 69g is added under stirring in batches
Zinc powder after TLC detects fully reacting, is filtered in 100 DEG C of reaction 1.5h, and solvent is concentrated under reduced pressure and obtains reduzate (IV)；
Proportion between all substances are as follows: oxidation product (III): formic acid: zinc powder=1:15:8
Step (4) hydrolysis decarboxylation:
Reduzate (IV) is moved in container four, the hydrochloric acid solution of 6N, mole of the hydrochloric acid and reduzate (IV) is added
Than for (10~12): 1,115 DEG C of reflux 1.5h are heated to, after TLC detects fully reactings, concentrated solvent uses ethanol/methylene
Recrystallize to obtain final product 5-aminoketoglutarate hydrochloride (5-ALA).
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