Cleaning of a kind of bulk drug--N-trimethyl lysine produced and application method
Technical field:
The present invention relates to a kind of clean method for producing of laminine, particularly in whole N-trimethyl lysine preparation process, adopt nontoxic, environmental protective type chemical raw material and modern ion exchange technique, not only guaranteed the specification of quality of N-trimethyl lysine, guaranteed that really the N-trimethyl lysine is a green product simultaneously as medicine or foodstuff additive.The N-trimethyl lysine both can be used as the bulk drug that prevents cardiovascular and cerebrovascular diseases, and the additive that can be used as food, healthcare products again uses.
Background technology:
Sea-tangle is a kind of edible algae that the public knows, and contains abundant nutrition.Contain a kind of non-protein amino acid with special physiological effect in the sea-tangle, i.e. N-trimethyl lysine is because of kelp is the another name of sea-tangle, so the N-trimethyl lysine also claims laminine.The N-trimethyl lysine has special blood pressure reduction effect, by reducing cholesterol, blood fat reducing, prevent the generation of blood vessel scleratheroma effect preventing hypertension and Intracerebral hemorrhage.The more important thing is that the N-trimethyl lysine is a kind of natural amino acid that is derived from the sea-tangle, thus as safe as a house to human body, have no side effect, be a kind of green cardiovascular and cerebrovascular bulk drug.
Hypertension becomes modern humans's a big healthy killer day by day, has become the public character health problem in China.China 1991 carries out sample survey to 940,000 people more than 15 years old, and the hypertension morbidity is 11.2%.Over nearly 20 years, China people are along with growth in the living standard, the increase of animal-derived food product, the change of food habits, and the quickening of life and work rhythm, the essential hypertension sickness rate has progressively ascendant trend, shows according to epidemiology survey, and China's hypertension is just to increase 3,000,000 people's speed development every year newly; 2003 120 first-aid centres in Qingdao City see and treat patients among the anxious danger of the 2600 many cases patient, and nearly 40% is the cardiovascular and cerebrovascular diseases patient.But present depressor mostly is the emergency medicine, is difficult to drug withdrawal in case take, and has not only caused heavy economical load to the patient, also produces the misery that complication increases the patient because of toxic side effect.Because of laminine is inherent one seed amino acid in the sea-tangle, so it is very high to take security.And laminine has the advantage for the treatment of both principal and secondary aspect of disease, so will play a positive role aspect prevention and the treatment cardiovascular and cerebrovascular diseases.But regrettably in the sea-tangle only there be about 3/10000ths the content of laminine, if extract from sea-tangle, not only causes a large amount of pollutions, does not also have industrial production because of cost is too high and be worth.If can produce laminine by manual simulation's synthetic method with suitable cost will be of great immediate significance.
At present, in existing technology, Chinese patent application CN 97123269.5 discloses a kind of preparation method of laminine, but adopt deleterious copper carbonate, methyl-sulfate and hydrogen sulfide in the building-up process as raw material, not only be difficult to guarantee quality, but also can cause defectives such as plant area and environmental pollution as the laminine of medicine.
Summary of the invention:
The objective of the invention is to overcome the weak point that prior art exists, a kind of Green Chemistry or cleaning chemistry (Green Chemistry, Clean Chemistry) technology is provided.Green Chemistry is exactly a measure from the source decontamination, and its content comprises new design or redesigns chemosynthesis, manufacture method and Chemicals eradicates source of pollution, is that ideal environmental pollution prevents method.Green Chemistry focuses on " safer " this notion.
In order to realize the foregoing invention purpose, the major measure that the present invention takes has: (1) design or redesign are to human health and the safer compound of environment, and this is the key component of Green Chemistry; (2) seek new, safer, more friendly to environment chemical synthesis route and production technique, this can start with from research, conversion basic raw material and initial compounds and the novel agent that induces one; (3) improve chemical reaction condition, reduce harm to human health and environment, reduce the production and the discharging of waste.Figure one is a cleaningization production technology principle synoptic diagram, and expression also comprises the reaction process of not having discharging or few discharging and recycle with nontoxic raw material decontamination.
Purpose of the present invention is exactly to follow the principle of Green Chemistry, has proposed new, safer, more friendly to environment chemical synthesis route and production technique, by introducing the production that cleans that novel agent and new technology have realized the N-trimethyl lysine.
The present invention has compared following advantage with existing patent:
(1) substitutes deleterious copper carbonate as the alpha-amino group sequestering agent in the reaction with food grade or feed level zinc sulfate;
(2) utilize environment-friendly industrial chemicals methylcarbonate to replace the methylating reagent of the big methyl-sulfate of contaminative as reaction;
(3) complexone with pharmaceutical grade replaces the hydrogen sulfide of severe toxicity as the alpha-amino group demasking agent in the reaction; Can not only guarantee quality, and eliminate the danger of polluting production plant and environment, realize the production that cleans of N-trimethyl lysine as the N-trimethyl lysine of medicine and foodstuff additive.
(4) utilize modern ion-exchange purification product technology, the quality of product N-trimethyl lysine is better.
The present invention compares with existing patent, except that the cleaning production method that discloses the N-trimethyl lysine, also discloses the application method and the purposes of N-trimethyl lysine.
The objective of the invention is to realize by following scheme:
With Methionin (I) is raw material, under alkaline pH=7.2-11 condition, generate intermediate product (II) with metallic salt generation alpha-amino group masking reaction, then on epsilon-amino, react the title complex (III) that generates quaternized lysine derivative with methylating reagent, then demask reaction and get N-trimethyl lysine crude product (IV) with complexing agent generation metal ion, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water or washing with alcohol purifying and product.Methionin adopts food grade or the pharmaceutical grade or the feed grade L lysine HCL of fermentative Production; Metallic salt can adopt Zn
2+Or Fe
2+Or Fe
3+Or Cu
2+Salt, as vitriol or muriate, first-selection is nontoxic zinc salt or molysite; Methylating reagent is for meeting the environmental protective type chemical material carbon dimethyl phthalate that the modern times " cleaning procedure " require; Complexing agent is for doing the edta and its sodium salt of medicine, and also available other complexing agent is as nitrilotriacetic acid(NTA) and sodium salt etc.Reaction principle is as follows:
In the formula: (I) Methionin
(II) Methionin metal complex
(III) N-trimethyl lysine metal complex
(IV) N-trimethyl lysine
Its operation steps and processing condition are
(1) shelter: L-Methionin or L lysine HCL (I) are 0.5~2: 1~4 with the mol ratio of metal-salt; L-Methionin or L lysine HCL are made into 0.1~30% the aqueous solution, are 7.2 to 11 with the sodium hydroxide solution adjust pH, under agitation add slowly to join in the metal salt solution, and the reaction times is 0.1-24 hour, product (II).
(2) methylate: the mol ratio by methylcarbonate and L-Methionin or L lysine HCL is 0.8~2: 13 metering methylcarbonates; Under high degree of agitation, methylcarbonate is slowly joined in product (II) reactor, keep 5~100 ℃ of temperature of reaction, 1~12 hour, obtain product (III).
(3) demask: by the salt of ethylenediamine tetraacetic acid (EDTA) or ethylenediamine tetraacetic acid (EDTA) and the mol ratio of L-Methionin or L lysine HCL is 1: 0.4~2 metering demasking agents; In reaction system, add demasking agent solid or solution, keep 5~75 ℃ of temperature of reaction, in 0.1~10 hour reaction times, obtain product (IV).
(4) ion-exchange is with refining: product (IV) is slowly passed through strong acidic ion resin (as the 732# Zeo-karb) exchange column, then product N-trimethyl lysine can be by resin absorption, through deionized water or washing with alcohol, again through ammoniacal liquor wash-out, negative pressure concentrate, crystallization and purifying.
Specific embodiments:
Below by specific embodiment the present invention is further elaborated.
Embodiment 1:
In the 500L reactor, add 300 kilograms of distilled water earlier, take by weighing 75 kilograms of food grade (feed grade) zinc sulfate and stir dissolving in 20 minutes, under agitation slowly add 91 kilograms of L lysine HCLs in the reactor again, 60 ℃ of isothermal reactions 1 hour allow Methionin and Zn
2+React completely; Then generate the title complex of quaternized lysine derivative with 135 kilograms of dimethyl carbonates, then demask reaction and get N-trimethyl lysine crude product with 79 kilograms of disodium EDTA generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water or washing with alcohol, negative pressure concentrate, crystallization and 110 kilograms of bulk drug N-trimethyl lysines.
Embodiment 2:
In the 100L reactor, add earlier 55 kilograms of distilled water, take by weighing 13 kilograms of drinking-water grade ferrous sulfates and stir dissolving in 20 minutes, under agitation 19 kilograms of L lysine HCLs are slowly added in the reactor again, 60 ℃ of isothermal reactions 1 hour allow Methionin and Fe
2+React completely; Then generate the title complex of quaternized lysine derivative with 27 kilograms of dimethyl carbonates, then demask reaction and get the laminine crude product with 16 kilograms of disodium EDTA generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water wash purifying, weak ammonia desorption, vacuum concentration, crystallization and 21 kilograms of bulk drug N-trimethyl lysines.
Embodiment 3:
In the 200L reactor, add earlier 100 kilograms of distilled water, take by weighing 27 kilograms of feed-grade bluestones and stir dissolving in 20 minutes, under agitation 37 kilograms of L lysine HCLs are slowly added in the reactor again, 60 ℃ of isothermal reactions 1 hour allow Methionin and Cu
2+React completely; Then generate the title complex of quaternized lysine derivative with 54 kilograms of dimethyl carbonates, then demask reaction and get the laminine crude product with 31 kilograms of disodium EDTA generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water wash purifying, weak ammonia desorption, vacuum concentration, crystallization and 40 kilograms of bulk drug N-trimethyl lysines.
Embodiment 4:
In the 150L reactor, add earlier 82 kilograms of distilled water, take by weighing 23.5 kilograms of feed level zinc sulfates, stir dissolving in 15 minutes, under agitation 25 kilograms of L lysine HCLs are slowly added in the reactor again, 55 ℃ of isothermal reactions 2 hours allow Methionin and Zn
2+React completely; Then generate the title complex of quaternized lysine derivative with 39.5 kilograms of dimethyl carbonates, then demask reaction and get N-trimethyl lysine crude product with 25.8 kilograms of tetrasodium salt of EDTA generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water wash purifying, weak ammonia desorption, vacuum concentration, crystallization and 30.5 kilograms of bulk drug N-trimethyl lysines.
Embodiment 5:
In the 1000L reactor, add earlier 720 kilograms of distilled water, take by weighing 135 kilograms of drinking-water grade ferrous sulfates and stir dissolving in 60 minutes, under agitation 189 kilograms of L lysine HCLs are slowly added in the reactor again, 56 ℃ of isothermal reactions 2.5 hours allow Methionin and Fe
2+React completely; Then generate the title complex of quaternized lysine derivative with 272 kilograms of dimethyl carbonates, then demask reaction and get the laminine crude product with 144.5 kilograms of nitrilotriacetic acid(NTA) sodium salt generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water wash purifying, weak ammonia desorption, vacuum concentration, crystallization and 216 kilograms of bulk drug N-trimethyl lysines.
Embodiment 6:
In the 300L reactor, add 160 kilograms of distilled water earlier, take by weighing 45.5 kilograms of feed level zinc sulfates and stir dissolving in 45 minutes, under agitation slowly add 48 kilograms of L-Methionins in the reactor again, 65 ℃ of isothermal reactions 70 minutes allow Methionin and Zn2+ react completely; Then generate the title complex of quaternized lysine derivative with 46 kilograms of dimethyl carbonates, then demask reaction and get the laminine crude product with 47 kilograms of disodium EDTA generation metal ions, utilize strong acidic ion resin exchange column absorption N-trimethyl lysine at last, through deionized water wash purifying, weak ammonia desorption, vacuum concentration, crystallization and 59.5 kilograms of bulk drug N-trimethyl lysines.
Embodiment 7:
In the 50L reactor, add earlier 27 kilograms of distilled water, take by weighing 6.7 kilograms of drinking-water grade ferrous sulfates and stir dissolving in 20 minutes, under agitation 8.1 kilograms of L lysine HCLs are slowly added in the reactor again, 60 ℃ of isothermal reactions 1 hour allow Methionin and Fe
2+React completely; Then generate the title complex of quaternized lysine derivative with 27 kilograms of dimethyl carbonates, then demask reaction and get the laminine crude product with 16 kilograms of disodium EDTA generation metal ions; Last earlier with strong acidic ion resin exchange column absorption N-trimethyl lysine, through deionized water wash, again with weak ammonia desorption, crystallization, purifying and 10 kilograms of foodstuff additive N-trimethyl lysines.
Purposes of the present invention is: the N-trimethyl lysine can be used as the bulk drug of preventing and treating hypertension, reducing blood-fat and maintenance blood vessel medicine or uses as foodstuff additive.
The present invention's prescription is: the consumption of preventing and treating laminine in hypertension, reducing blood-fat and the maintenance blood vessel medicine composition is 0.001%-100%, and the formulation of medicine is capsule, tablet, pulvis and used for intravenous injection injection; The consumption of N-trimethyl lysine is 0.0001%-50% in the food formulations.