CN1219760C - Methyleneseleno propanel method for preparing selenoic methionine - Google Patents
Methyleneseleno propanel method for preparing selenoic methionine Download PDFInfo
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- CN1219760C CN1219760C CN 02104260 CN02104260A CN1219760C CN 1219760 C CN1219760 C CN 1219760C CN 02104260 CN02104260 CN 02104260 CN 02104260 A CN02104260 A CN 02104260A CN 1219760 C CN1219760 C CN 1219760C
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- selenomethionine
- methionine
- methyleneseleno
- propanel
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Abstract
The present invention belongs to the fields of amino acid medicines, and more specifically, the present invention relates to the preparation of selenomethionine by using a chemically synthesized methyleneseleno propanel method. Methyl hydroselenide, acrolein and related compounds are used to synthesize methyleneseleno propanel which is an important intermediate body in the process of preparing the selenomethionine, and the methyleneseleno propanel is used to substitute for the methyleneseleno propanel which is the intermediate body of a methionine producing technology line; thus, the selenomethionine can be easily synthesized by using a biologic microelement selenium and methionine by chemical synthesis in the methionine producing technology line. The selenomethionine has multiple kinds of biological activity that the sulfur-contained methionine does not have, particularly para-insulin action; thus, the selenomethionine can be made into oral taking medicines for treating diabetes. Therefore, the selenomethionine has the function of replacing insulin.
Description
(1) technical field:
The invention belongs to the amino acid drug field, relate to chemosynthesis intermediate Methyleneseleno propanel method for preparing selenoic methionine;
The para-insulin effect that the invention still further relates to biologic trace element and amino acid coordination compound selenomethionine is used for the treatment of the technology of diabetes.
(2) background technology:
As everyone knows, exist with the form that contains selenoamino acid because the important biomolecule activity of trace element-selenium is many in vivo, particularly selenomethionine is widely used for departments such as medicine, health care, agricultural and nutrition, and the preparation method of selenomethionine comes into one's own.
1, prior art:
(1) liquid ammonia process for caustic soda purification (Na/ligNH
4) the preparation selenomethionine: in order to obtain selenomethionine, adopt (selenium)-benzyl seleno homocysteine by sodium/liquefied ammonia usually, reduction excision benzyl methylates again.(Xu Huibi chief editor.The chemistry of selenium, biological chemistry and the application in life science thereof.The 50th page, Wuhan: press of HUST, 1994.)
(2) biological synthesis process prepares selenomethionine: with fermentation method and Production by Enzymes selenomethionine.Because the fermentation method processing condition are difficult to management, product yield is low, the scale operation income is little.
2, the defective of prior art:
No matter existing selenomethionine preparation method is the processing condition complexity of chemical synthesis or biological synthesis process reaction, and management is difficult; Product concentration is low, yield is low; Equipment scale is big, income is little.Therefore, the selenomethionine product can't satisfy the supply and demand in market, and has limited the exploitation of selenium methionine for analogue.
(3) summary of the invention:
1, invent the problem that will solve:
The objective of the invention is, by the methylthiopropionaldehyde in synthetic important intermediate first seleno propionic aldehyde replacement methionine(Met) (methionine(Met)) technological line, realize producing selenomethionine with the operational path of producing methionine(Met), the present invention is referred to as first seleno propionic aldehyde method.
Another object of the present invention is, the selenomethionine with para-insulin effect is provided, and makes oral hypoglycemic by preparation technique and replaces Regular Insulin and other antidiabetic drugs treatment diabetes.
2, solve the problem method:
Technical scheme of the present invention is achieved in that the characteristics that all exist similarity according to the organic compound that contains selenium and sulfur-containing amino acid on chemical property still is synthetic method, replaces methylthiopropionaldehyde by synthetic important intermediate first seleno propionic aldehyde.This method is the key link of forerunner's chemosynthesis in the process of selenomethionine, the synthetic of propenal and methyl-hydroselenide reaction just important intermediate first seleno propionic aldehyde.Specifically, be exactly at first to prepare selenourea (organic reagent synthetic, Beijing: Maritime Press, 1984 such as to lift a sail with thiocarbamide.), further prepare methyl-hydroselenide again according to the thiomethyl alcohol production technique.Wherein, the selenourea methylation reaction can replace methyl-sulfate with the selenic acid dimethyl ester.
The preparation of described first seleno propionic aldehyde is:
Reaction equation:
(propenal) (methyl-hydroselenide) (first seleno propionic aldehyde)
Synthesizing of [attached] methyl-hydroselenide
Put on display important methylthiopropionaldehyde production December nineteen eighty-three in international chemical process of Paris, FRA and equipment expo and simplified, produced the methionine(Met) new technological process, the glycolylurea method that is exactly domestic and international mostly usefulness is produced methionine(Met) technical matters and flow process.Therefore, first seleno propionic aldehyde method of the present invention is transplanted to the production of selenomethionine on the glycolylurea method operational path and technological process of chemosynthesis methionine(Met), can also use chemical synthesiss such as malonic ester method.
(4) embodiment:
The method that methionine(Met) is produced in chemosynthesis mainly contains Strecker method, malonic ester, amino lactone process and glycolylurea method, mostly adopts the glycolylurea method both at home and abroad.The important intermediate methylthiopropionaldehyde of glycolylurea method and malonic ester method wherein, replace thiomethyl alcohol and the synthetic first seleno propionic aldehyde intermediate of acrolein reaction with methyl-hydroselenide, be implemented in chemosynthesis selenomethionine, i.e. Methyleneseleno propanel method for preparing selenoic methionine on the methionine(Met) production line.
Manufacture method:
Operational path:
Technological process:
1, dehydration: yield 95% (in propylene) or 70% (in glycerine), ratio of components, glycerine: sal enixum: vitriolate of tartar=1: 0.5: 0.26.Earlier the glycerine of 1/7 amount and whole sal enixum, vitriolate of tartar are dropped in the reactor, begin to drip remaining glycerine when being warmed up to 190 ℃, the propenal gas that reaction generates is led through condenser condenses, be collected in the basin, the propenal crude product.
Crude product is added 10% ammonium bicarbonate soln P
HBe 6, carry out fractionation, collecting 50～75 ℃ of cuts is the propenal elaboration, and 75～90 ℃ of cuts are high boiling product, waits until down batch merging fractionation, and the raffinate more than 95 ℃ discards.
2, addition: yield 94% (to propenal), ratio of components, propenal: methyl-hydroselenide: neutralized verdigris: formic acid=1: 0.1: 0.01: 0.024.
Propenal and formic acid input addition tower (being first seleno propionic aldehyde synthetic tower) are under agitation added neutralized verdigris, be heated to 35～41 ℃, in addition selenol is fed in the synthetic tower, make its reaction, weigh 1.066～1.074/20 ℃ the time to the reaction solution ratio, reaction finishes, first seleno propionic aldehyde.
3, cyclization: ratio of components, first seleno propionic aldehyde: sodium cyanide: bicarbonate of ammonia=1: 0.52: 1.75.
Bicarbonate of ammonia is dropped in the retort, add the ordinary water that is equivalent to 4 times of basic weight amounts, stirring makes it dissolving, with after the ordinary water dissolving of sodium cyanide with 3 times of its weight, after stirring in the input jar, under agitation slow overflowing drips first seleno propionic aldehyde again, after the titration, be warming up to 75～80 ℃, reacted 3 hours, get first selenium ethyl glycolylurea solution (abbreviation uride).
4, hydrolysis: ratio of components, uride (by first seleno propionic aldehyde): sodium hydroxide (28%): gac=1: 2.75: 0.1.
Uride and sodium hydroxide solution (28%) are added in the autoclave, and the joint door is closed in the ammonia excretion 1 hour that is hydrolyzed that heats up, and continues heat temperature raising, is warmed up to 160 ℃ gradually, at this temperature and 5.5kg/cm
2Under the pressure, react 1 hour selenomethionine salt.
5, neutralization: selenomethionine salt blowing in neutralization tank, is added an amount of steaming and stays water dilution with till not going out crystallization, add hydrochloric acid and transfer P
H5～6, add gac and boil decolouring in 45 minutes, to filter, filtrate concentrating separated out crystallization, changes in the crystallizer, starts stirring, boils, decolours 1.5 hours, and 15～20 ℃ of insulations are filtered, the filtrate crystallisation by cooling, drying gets the selenomethionine finished product.
Selenomethionine is the selenium-containing compound with multiple biological effect, take the course of its own in the aspects such as application that remove free radical, antitumous effect, trophism in antioxygenation, prevent and treat endemy and husbandry, be that methionine(Met) is not available, particularly the discovered in recent years selenide have lowering blood glucose and regulation and control insulin-mediated metabolic process in have the para-insulin effect, can replace insulin for treating diabetes.Far beyond Sodium Selenite etc. significantly, particularly the inventor replaces insulin action more effective in the preparation and the application (number of patent application 98120472.4) of the chromium selenomethionine of preceding application to selenomethionine aspect multiple biological activity.
Introduce the test-results of The compounds of this invention selenomethionine hypoglycemic activity below.
Acute toxicity test: rats by intraperitoneal injection DL-selenomethionine minimum lethal dose (MLD) is the 10.54mg/kg body weight.
Hypoglycemic drug effect is learned test: select the rat (body weight 200-220g) of male and female half and half to carry out hypoglycemic para-insulin effect test.
With 10 rat fasting 6 hours, behind the survey blood glucose value, be divided into treatment group and control group at random before the test, every group of each 5 rat are brought out the rat hyperglycemia with the tetraoxypyrimidine chemical reagent.
The continuous 16 days selenomethionines to diabetes rat abdominal injection 15 μ mol/kg body weight are organized in treatment; Control group diabetes rat abdominal cavity gives the water for injection with amount, and the result is as table.
Table. selenomethionine is to the test-results of diabetes rat hypoglycemic
| Group | Rat blood sugar (mg/dl) before the treatment | Treatment back rat blood sugar (mg/dl) | The P value | |||
| The normal rat number | X±S | The diabetes rat number | X±S | |||
| Selenomethionine group control group | 5 5 | 201±20 198±18 | 5 5 | 204±23 268±35 | ＜0.01 | |
The blood sugar recovery of treatment group rat is to the normal value level, and the blood glucose value of control group diabetes rat is still kept the hyperglycemia level, two groups of significant differences, P＜0.01.Therefore, can judge that selenomethionine can replace Regular Insulin to play the metabolism of regulating and controlling blood sugar in vivo, experimental results show that to have the para-insulin effect.
More than experiment prompting, the para-insulin effect that selenomethionine shows can replace insulin for treating diabetes, with the first trivalent chromium synthetic compound chromium selenomethionine treatment of life trace diabetes, provides new scenario.
(5) invention effect:
First seleno propionic aldehyde of the present invention is the important intermediate in the preparation selenomethionine process, replace the important intermediate methylthiopropionaldehyde of making methionine(Met) with it, realize the chemosynthesis Methyleneseleno propanel method for preparing selenoic methionine at the maturation process route of producing methionine(Met).
Selenomethionine shows good multiple biological activity, and particularly the para-insulin effect is used for the treatment of diabetes, and the present invention also is used for selenomethionine medicine, nutritive health-care and agricultural etc.
Claims (5)
1. the synthetic method of a selenomethionine may further comprise the steps:
(1) carries out addition reaction with methyl-hydroselenide and propenal, obtain first seleno propionic aldehyde;
(2) product of step (1) obtains first selenium ethyl glycolylurea through ring-closure reaction;
(3) product of hydrolysing step (2) obtains selenomethionine sodium;
(4) product of neutralization procedure (3) obtains the selenomethionine product.
2. the method for claim 1 is characterized in that step (1) is in the presence of neutralized verdigris and formic acid, and carry out propenal under 35-41 ℃: methyl-hydroselenide: neutralized verdigris: the ratio of components of formic acid is 1: 0.1: 0.01: 0.024..
3. the method for claim 1 is characterized in that step (2) is in the presence of sodium cyanide and bicarbonate of ammonia, carries out under 75-80 ℃, and first seleno propionic aldehyde: sodium cyanide: the ratio of components of bicarbonate of ammonia is 1: 0.52: 1.75.
4. the method for claim 1 is characterized in that in step (3), and the sodium hydroxide solution of use 28% is hydrolyzed.
5. the method for claim 1 is characterized in that in step (4), adds hydrochloric acid, at P
HAdd the gac boiling decoloring 5～6 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02104260 CN1219760C (en) | 2002-02-28 | 2002-02-28 | Methyleneseleno propanel method for preparing selenoic methionine |
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| CN 02104260 CN1219760C (en) | 2002-02-28 | 2002-02-28 | Methyleneseleno propanel method for preparing selenoic methionine |
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| CN1369483A CN1369483A (en) | 2002-09-18 |
| CN1219760C true CN1219760C (en) | 2005-09-21 |
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| CN 02104260 Expired - Fee Related CN1219760C (en) | 2002-02-28 | 2002-02-28 | Methyleneseleno propanel method for preparing selenoic methionine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109160894A (en) * | 2018-10-15 | 2019-01-08 | 禄丰天宝磷化工有限公司 | A kind of DL-2- amino -4- first seleno butyric acid production technology of environment-protecting clean |
| CN109369481A (en) * | 2018-10-15 | 2019-02-22 | 禄丰天宝磷化工有限公司 | A kind of method of the preparation and stable storage of DL-2- hydroxyl -4- first seleno butyronitrile |
| CN109160893A (en) * | 2018-10-15 | 2019-01-08 | 禄丰天宝磷化工有限公司 | A kind of preparation method of first seleno propionic aldehyde |
| CN109232342A (en) * | 2018-10-15 | 2019-01-18 | 禄丰天宝磷化工有限公司 | A kind of preparation method of selenomethionine hydroxy analogs |
| CN110078649A (en) * | 2019-04-15 | 2019-08-02 | 四川尚元惠生生物科技有限公司 | A kind of preparation method of high-purity selenomethionine |
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