CN109438307A - A kind of preparation method of L- selenomethionine - Google Patents
A kind of preparation method of L- selenomethionine Download PDFInfo
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- CN109438307A CN109438307A CN201811492865.9A CN201811492865A CN109438307A CN 109438307 A CN109438307 A CN 109438307A CN 201811492865 A CN201811492865 A CN 201811492865A CN 109438307 A CN109438307 A CN 109438307A
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- diketopiperazine
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C391/00—Compounds containing selenium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Abstract
The present invention provides a kind of preparation methods of L- selenomethionine, comprising the following steps: A) by sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtain 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine；B 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution), obtains L- selenomethionine.The present invention is with 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine replaces with nucleopilic reagent methyl-hydroselenide salt as reaction substrate, hydrolysis, neutralizes obtained L- selenomethionine, simple process, reaction condition are mild, product is single, easily separated, yield is high, are suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of fine chemical synthesis more particularly to a kind of preparation methods of L- selenomethionine.
Background technique
Selenium is the essential trace elements of the human body, is the important component of a variety of enzymes of human body, once human body selenium deficiency, Jiu Huizhi
Connecing leads to cardiovascular and cerebrovascular diseases, hypertension, metabolic syndrome, enterogastric diseases, diabetes, asthma, Parkinson's disease, hepatopathy, cancer
Deng the generation of more than 40 kinds of diseases, to lead to the generation of more than 400 kinds of diseases indirectly.Therefore, great function of the selenium to human health
It is that other substances are irreplaceable.The data that the World Health Organization announces shows that the whole world has a countries and regions more than 40 different
The selenium deficiency of degree, the area in China 2/3 belong to selenium deficiency area, the 29.00% serious selenium deficiency in area, so living in this area
Crowd must meet intracorporal nutritional need by Selenium Supplement, and currently used selenium-supply product is mainly that inorganic sodium selenite is worked as
Selenium-supply product used in preceding mainly has inorganic selenium and two kinds of organic selenium, and common inorganic selenium is inorganic sodium selenite and sodium selenate
The food and health care product (such as: sodium selenite piece, selenium-rich salt, selenium Bao Kang, gold partner) of reinforcing, organic selenium-are mainly selenium
Albumen, it is to be present in plant animal protein in the form of two kinds of selenocysteine (SeCys) and selenomethionine (SeMet)
In.
It has been proved that selenium toxicity size and bioavailability and its chemical form in relation to the absorption in vivo of: inorganic selenium,
Utilization rate is low and is more toxic, and toxic dose and human body requirement are very close, thus its usage amount is strictly limited；With it is inorganic
Selenium is compared, and the maximum feature of organic selenium is absorption of human body, utilization rate height, and bioactivity is strong, Small side effects, therefore organic selenium product
Developmental research have received widespread attention.The approach for obtaining organic selenium at present mainly has extraction, fermentation and chemical synthesis, extracts
Method because the restricted of natural organic selenium resource, Se content are low, extraction process is complicated, yield is low, it is at high cost, be not able to satisfy human body battalion
Feeding needs；Fermentation method is using inorganic selenium sodium selenite as raw material, by biofermentation, converts organic selenium, the party for inorganic selenium
Main problem existing for method is that inorganic selenium conversion ratio is low during the fermentation, and a large amount of inorganic seleniums are discharged with waste water formation, cause ring
Border pollution, while the form of product, purity are unstable, quality hardly results in guarantee；And chemical synthesis prepares organic selenizing and closes
Object, Se content is high, production cost is low and is able to satisfy the nutritional need of human body, practicable approach of also can yet be regarded as.
L- selenomethionine is the existence form of one of the most common type selenium in nature, in natural plants and grain component
Most of organic seleniums exist in the form of L- selenomethionine, and compared with inorganic selenium, selenomethionine has small toxicity, environmental pollution
Small, the advantages that bioavailability is high.Currently, American-European many countries advocate energetically and use organic selenium, as Sweden requires sucking pig to raise
Organic selenium must be used in material；Inorganic selenium is forbidden to use in Japanese regulation feed.Selenomethionine property is stablized, and effect is aobvious
It writes, practical value with higher, popularization and application foreground is wide.
Currently, the synthetic method of L- selenomethionine be summarized as it is following several:
The first: glycolylurea method
The method is to imitate the glycolylurea method method for preparing methionine, using methacrylaldehyde and methyl-hydroselenide as raw material, after addition, with
NaCN reaction cyclization, then hydrolysis, acidification obtain target product.The method reaction step is long, and raw material methyl-hydroselenide source is limited,
And violent in toxicity Cymag is used, it is very risky in terms of safe and environment-friendly and occupational health.
Second: amino butyrolactone method
1) using gamma-butyrolacton as starting material, alpha-amido-MCPB-butyric acid) lactone hydrobromate is generated through α-bromination, ammonolysis,
Open loop is reacted with sodium methyl-hydroselenide again and obtains selenomethionine, total recovery about 33%, the technique is because using high volatility, toxicity big
Bromine, operation difficulty is big, and equipment requirement is high；It is seriously polluted simultaneously, expenses of environmental protection is high, and obtained final product is DL- seleno
Methionine needs to split.
2) it using methionine as starting material, is hydrolyzed with iodomethane or dimethyl sulfate methylation of ester, desulfurization, α-ammonia is made in cyclization
Base-gamma-butyrolacton hydrochloride, then reacts open loop with sodium methyl-hydroselenide and obtains selenomethionine.This method yield has biggish mention
Height, but it is alkylating reagent that shortcoming, which is big using expensive, toxicity and highly volatile iodomethane, and purifies post-processing
Process is complicated, and product yield is low.
The third: 4- halogen -2-amino-butyric acid derivative method
1) Painter first prepares Se- benzyl seleno homocysteine and uses Na/NH again3(liquid) reduction excision benzyl, is then used
Iodomethane methylates to obtain target product, and total recovery is up to 84%；Se-Se homocystine can also be first generated, then uses Na/NH3
Methylate obtained selenomethionine again after (liquid) reduction disconnection Se-Se key, and this method severe reaction conditions use metallic sodium and liquid
Ammonia needs special reaction device；Raw material substrate is limited without industrial goods, source, and prepares difficult.
2) Troels et al. is methylated, NaHCO using methionine as starting material with iodomethane3Solution hydrolysis, HCl acid
Chemical conversion ring, HBr/HAc open loop, acid catalyzed esterification obtain the bromo- 2-amino-butyric acid methyl ester hydrochloride intermediate of 4-, are re-introduced into first seleno
Afterwards, 7 steps of hydrolysis react to obtain target compound, and total recovery is less than 30%.Safety in utilization is extremely low, expensive in the technique
Chemical reagent lithium methide and tributoxy-boron, and anhydrous, oxygen free operation is required, it is very high to equipment requirement, it is difficult to realize scale
Metaplasia produces.
3) nucleopilic reagent sodium methyl-hydroselenide is prepared with dimethyl diselenide ether and sodium borohydride reaction, replaces the bromo- α-ammonia of substrate 4-
Then bromine in base acid esters hydrolyzes to obtain selenomethionine.Although method description is simple, dimethyl diselenide ether and 4- are not specified
The source of bromo- butyrine ester, and both sold without industrial goods, preparation process is complicated.
From the above synthetic method, it is not difficult to find out that, in existing synthesis technology, mostly there is it is seriously polluted, at high cost,
Low yield, product need to split, are difficult to realize the problems such as industrialization.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation method of L- selenomethionine, the preparation method in the present invention is to ring
Border is friendly, raw material is cheap and easy to get, yield is high and product is single configuration, without splitting.
The present invention provides a kind of preparation method of L- selenomethionine, comprising the following steps:
A) by sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtains 3,6-
Two-(2- first selenium ethyl) -2,5- diketopiperazines；
B) 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution,
Obtain L- selenomethionine.
Preferably, the sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine molar ratio be 1:(0.4~
0.5)。
Preferably, the temperature of the nucleophilic substitution is 20~90 DEG C；
The time of the nucleophilic substitution is 3~12 hours.
Preferably, the concentration of the hydrochloric acid solution is 4~12mol/L.
Preferably, the ratio between the quality and the volume of hydrochloric acid solution of 3,6-, bis--(2- first selenium ethyl) -2, the 5- diketopiperazine
For 1g:(6~40) mL.
Preferably, the temperature of the hydrolysis is 115~120 DEG C；
The time of the hydrolysis is 3~5 hours.
Preferably, 3,6-, bis--(2- chloroethyl) -2, the 5- diketopiperazine is prepared according to the following steps to obtain:
L-Aspartic acid is esterified under the effect of the catalyst with alcohol, obtains esterification products；
The esterification products are cyclized under conditions of being heated to reflux, obtained cyclic products and reducing agent and activation
Agent mixing, is restored, obtains 3,6- bis--(2- ethoxy) -2,5- diketopiperazine；
Obtained 3,6- bis--(2- ethoxy) -2,5- diketopiperazine is mixed with chlorinating agent, chlorination is carried out, obtains 3,6-
Two-(2- chloroethyl) -2,5- diketopiperazines.
Preferably, alcohol used in the esterification is one or more of methanol, ethyl alcohol, the tert-butyl alcohol and benzylalcohol；
Catalyst used in the esterification be hydrochloric acid, sulfuric acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, thionyl chloride, highly acid from
One or more of sub-exchange resin and lewis acid.
Preferably, the reducing agent is sodium borohydride and/or potassium borohydride；
The cyclic products and the molar ratio of reducing agent are 1:(4~6).
Preferably, the chlorinating agent is one or more of phosphorus pentachloride, phosphorus trichloride and thionyl chloride；
The temperature of the chlorination reaction is 0~40 DEG C；
The time of the chlorination reaction is 1~5 hour.
The present invention provides a kind of preparation methods of L- selenomethionine, comprising the following steps: A) by sodium methyl-hydroselenide and 3,
6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtains 3,6- bis--(2- first selenium ethyl) -2,5- diketone
Piperazine；B) 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution, obtained
To L- selenomethionine.The present invention with 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine as reaction substrate, with nucleopilic reagent
Methyl-hydroselenide salt replace, hydrolysis, neutralize be made L- selenomethionine, simple process, reaction condition are mild, product is single, it is easily separated,
Yield is high, is suitble to industrialized production.The experimental results showed that the yield of the L- selenomethionine in the present invention is up to 82.5%, than
Optical activity is up to [ɑ]D 20=+18.2 ° (C=0.5,1MHCl).
Further, the present invention uses L-Aspartic acid for starting material synthetic reaction substrate 3,6- bis--(2- chloroethene
Base) -2,5- diketopiperazine, also, the preparation of sodium methyl-hydroselenide does not need to be separated directly and substrate reactions in the present invention, can overcome in this way
The shortcomings that unstability of sodium methyl-hydroselenide, difficult separating-purifying.
Specific embodiment
The present invention provides a kind of preparation methods of L- selenomethionine, comprising the following steps:
A) by sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtains 3,6-
Two-(2- first selenium ethyl) -2,5- diketopiperazines；
B) 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution,
Obtain L- selenomethionine.
The present invention does not have special limitation to the source of 3,6-, bis--(2- chloroethyl) -2, the 5- diketopiperazine, preferably presses
According to the synthesis route in the present invention, using L-Aspartic acid as starting material, esterification, cyclisation and reduction, chlorination are passed sequentially through
It is prepared.
Specific preparation process is as follows:
L-Aspartic acid is esterified under the effect of the catalyst with alcohol, obtains esterification products；
The esterification products are cyclized under conditions of being heated to reflux, obtained cyclic products and reducing agent and activation
Agent mixing, is restored, obtains 3,6- bis--(2- ethoxy) -2,5- diketopiperazine；
Obtained 3,6- bis--(2- ethoxy) -2,5- diketopiperazine is mixed with chlorinating agent, chlorination is carried out, obtains 3,6-
Two-(2- chloroethyl) -2,5- diketopiperazines.
The reaction equation for preparing 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is shown in formula I:
Preferably under conditions of oil bath heating flows back, L-Aspartic acid is carried out under the effect of the catalyst with alcohol by the present invention
Esterification, obtains esterification products；
In the present invention, the alcohol is preferably one or more of methanol, ethyl alcohol, the tert-butyl alcohol and benzylalcohol,
More preferably benzylalcohol, i.e. benzyl alcohol；The catalyst is preferably hydrochloric acid, sulfuric acid, benzene sulfonic acid (PhSO3H), to toluene
Sulfonic acid (p-TsOH), thionyl chloride (SOCl2), one or more of strong-acid ion exchange resin and lewis acid.
In the present invention, the molar ratio of the L-Aspartic acid and alcohol is preferably 1:(1~5), more preferably 1:(2~4),
Most preferably 1:(2.88~3)；The molar ratio of the L-Aspartic acid and the catalyst is preferably 1:(0.5~3), more preferably
For 1:(1~2).
The present invention does not have special limitation to the time of the esterification, and oil bath heating reflux in reaction system until do not have
Until thering is water to steam, it can stop reacting.
Since the catalyst in the present invention is acid, the esterification products that L-Aspartic acid obtains after esterification
For the salt of L-Aspartic acid corresponding esters.Before carrying out next step cyclization, the present invention will preferably take in the esterification products
Preferably the esterification products are added in unsaturated carbonate potassium solution by sulfonate groups removal in the catalyst of band, the present invention, stirring,
And extraction 3 times is carried out using ethyl acetate, merge organic phase, successively using saturated common salt water washing, anhydrous magnesium sulfate drying, mistake
Filter and reduced pressure removal solvent, obtain the esterification products of L-Aspartic acid.
Preferably toluene will be added in the esterification products in the present invention, is heated to reflux 24~48 hours, is cyclized, obtains ring
Change product；
Then reducing agent and activator are added in the cyclisation product, is restored, obtains 3,6- bis--(2- hydroxyl second
Base) -2,5- diketopiperazine.
The reducing agent is preferably sodium borohydride and/or potassium borohydride；The activator is preferably methanol and/or ethyl alcohol；
The cyclic products and the molar ratio of reducing agent are preferably 1:(4~6), more preferably 1:5；The cyclic products and activator
Molar ratio is preferably 1:(5~20), more preferably 1:(10~15).
The temperature of the reduction reaction is preferably 20~35 DEG C, and more preferably 25~30 DEG C；The time of the reduction reaction
Preferably 1~5 hour, more preferably 2~3 hours.
After reduction reaction, the present invention is mixed by obtained 3,6- bis--(2- ethoxy) -2,5- diketopiperazine and chlorinating agent
It closes, carries out chlorination, obtain reaction substrate 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine.
Preferably under conditions of ice bath is cooling, obtained 3,6- bis--(2- ethoxy) -2,5- diketopiperazine is added by the present invention
Enter in chlorinating agent, stir evenly, be then to slowly warm up to room temperature, continue stirring 0.5~1 hour, is further continued for being to slowly warm up to 35
~40 DEG C, stirring carries out reaction 0.5~1 hour, is cooled to room temperature reaction system after fully reacting, obtains reaction substrate 3,
6- bis--(2- chloroethyl) -2,5- diketopiperazine.
In the present invention, the chlorinating agent is preferably phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3) and thionyl chloride
(SOCl2One or more of)；The molar ratio of 3,6-, bis--(2- ethoxy) -2, the 5- diketopiperazine and chlorinating agent is preferred
For 1:(10~30), more preferably 1:(20~25).
The present invention does not have special limitation to the source of the sodium methyl-hydroselenide, preferably prepares according to following steps in the present invention
It obtains:
Under conditions of nitrogen protection, dimethyl diselenide ether is mixed in a solvent with reducing agent, is reacted, obtains first
Selenol sodium；Metallic sodium is preferably first dissolved in methanol by the present invention, is generated sodium methoxide, is then sequentially added reducing agent and dimethyl
Diselenide is reacted, and sodium methyl-hydroselenide is obtained.
The reaction equation of sodium methyl-hydroselenide is prepared as shown in Formula II:
In the present invention, the reducing agent is preferably sodium borohydride, mole of the dimethyl diselenide ether and sodium borohydride
Than being preferably 1:(2~4), more preferably 1:(2.5~3)；The solvent is preferably methanol and/or ethyl alcohol, the temperature of the reaction
Preferably 50~60 DEG C, more preferably 58~60 DEG C of degree；The time of the reaction is preferably 1~2 hour.
After obtaining sodium methyl-hydroselenide, the present invention preferably directly adds 3,6-, bis--(2- chloroethyl) -2, the 5- diketopiperazine
Enter into the preparation system of sodium methyl-hydroselenide, carry out nucleophilic substitution, that is to say, that the present invention be prepared sodium methyl-hydroselenide it
Afterwards, sodium methyl-hydroselenide product is not separated, directly carries out " cooking different foods in one pot " with reaction substrate and react, sodium methyl-hydroselenide can be overcome in this way
Unstability, difficult separating-purifying the shortcomings that.
The equation of the nucleophilic substitution is as shown in formula III:
In the present invention, the sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine mole
Than being preferably 1:(0.3~0.5), more preferably 1:(0.4~0.48)；The temperature of the nucleophilic substitution is preferred
It is 20~90 DEG C, more preferably 30~80 DEG C, most preferably 40~70 DEG C；The time of the nucleophilic substitution is preferably 3~
12 hours, more preferably 3~10 hours, most preferably 3~5 hours.
After completing the nucleophilic substitution, the present invention is by obtained 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine
It is dissolved in hydrochloric acid solution, is hydrolyzed；
After hydrolysis completely, the reaction system evaporated under reduced pressure solvent that the present invention will preferably obtain, the hydrochloric acid that will dissociate in system
It removes；The hydrolysate obtained at this time is the hydrochloride of L- selenomethionine, and alkaline reagent is added in the present invention in hydrolyzation system,
Hydrochloric acid is neutralized, L- selenomethionine is obtained.
The equation of the hydrolysis is as shown in formula IV:
In the present invention, the concentration of the hydrochloric acid solution is preferably 4~12mol/L, more preferably 6~10mol/L；It is described
The ratio between quality and the volume of hydrochloric acid solution of 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazines are preferably 1g:(6~40) mL,
More preferably 1g:(10~40) mL, most preferably 1g:(20~40) mL.
In the present invention, the temperature of the hydrolysis is preferably 115~120 DEG C；The time of the hydrolysis is preferred
It is 3~5 hours.
In the present invention, the alkaline reagent is preferably one or more of ammonium hydroxide, triethylamine and pyridine, the present invention couple
The dosage of the alkaline reagent does not have special limitation, and the pH value of system can be adjusted in 5.0~6.0 ranges.
It is added after alkaline reagent adjusts the pH value of system, the present invention is preferably by the solid filtering of precipitation, with water-second
Alcohol recrystallization, obtains L- selenomethionine.
The present invention provides a kind of preparation methods of L- selenomethionine, comprising the following steps: A) by sodium methyl-hydroselenide and 3,
6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtains 3,6- bis--(2- first selenium ethyl) -2,5- diketone
Piperazine；B) 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution, obtained
To L- selenomethionine.The present invention with 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine as reaction substrate, with nucleopilic reagent
Methyl-hydroselenide salt replace, hydrolysis, neutralize be made L- selenomethionine, simple process, reaction condition are mild, product is single, it is easily separated,
Yield is high, is suitble to industrialized production.The experimental results showed that the yield of the L- selenomethionine in the present invention is up to 82.5%, than
Optical activity is up to [ɑ]D 20=+18.2 ° (C=0.5,1MHCl).
In order to further illustrate the present invention, with reference to embodiments to a kind of system of L- selenomethionine provided by the invention
Preparation Method is described in detail, but cannot be understood as limiting the scope of the present invention.
Embodiment 1
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1,3,6- bis--(2- chloroethyl) -2,5- diketopiperazine preparation
1) it is esterified
Electric stirring is being housed, in the round-bottomed flask of reflux condensing tube, 66.5 grams of L-Aspartic acid, p- is added in water segregator
TsOH.H290 grams of O, benzyl alcohol 150mL and 500mL benzene.Oil bath heating reflux stops reaction until not having water to steam,
It steams most of benzene and the ether of 1:1 and the mixed liquor 500mL of petroleum ether is added after cooling, be put into refrigerator overnight, white is precipitated
Crystal, filtering are recrystallized with 1:1 ethyl alcohol and ether mixed liquor, obtain L-Aspartic acid dibenzyl ester tosilate 202g, are received
Rate 82.6%,
Fusing point m.p. is 150~152 DEG C, CHC13:CH3OH=7:1Rf=0.68, specific rotatory power [α]D 20=+0.9 ° of (C=
1,CH3OH)。
2) cyclisation and reduction
In the round-bottomed flask of 1000mL, L-Aspartic acid dibenzyl ester tosilate 100g is added, saturated carbon is added
Sour potassium solution 250mL after stirring 20min, is extracted with the ethyl acetate of 500mL × 3, merges organic phase, with saturated common salt water washing,
Anhydrous magnesium sulfate, which dries, filters, is concentrated under reduced pressure to give light yellow oil L-Aspartic acid dibenzyl ester 57g (yield 95%).
Electric stirring is being housed, is sequentially adding L-Aspartic acid dibenzyl ester 47g, toluene in the three-necked flask of reflux condensing tube
300mL is heated to reflux for 24 hours under stirring, is cooled to room temperature, and washes, and separation is added sodium borohydride 11.5g, starts stirring, slowly
Methanol 55mL is added dropwise, about 1h is dripped off, and is continued to stir 1h, is concentrated under reduced pressure into small size, residue is put into refrigerator, there is white crystal analysis
Out, it filters, it is dry, 3,6- bis--(2- ethoxy) -2,5- diketopiperazine crude product 11.2g is obtained, being not required to purification can directly use
In the next step.
3) chlorination
Electric stirring is being housed, in the three-necked flask of reflux condensing tube, thionyl chloride 74mL is added, under ice bath is cooling, delays
It is slow that 2) step product 10g is added, after mixing evenly, it is slowly warmed to room temperature stirring 1h, it is further heated up to 37 DEG C of stirring 1h, are cooled to
Anhydrous ether 250mL dilution is added in room temperature, and filtering, ether is washed twice, placed in draught cupboard, after sulfoxide to be chlorinated is evaporated completely,
It is washed with water, filtered and dried, obtains faint yellow 3,6-, bis--(2- chloroethyl) -2,5- diketopiperazine product 11g, m.p.230-231 DEG C, receive
Rate 93.0%.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 200mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then it is cooled at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, is heated to reflux stirring
3h to 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), is filtered, filtrate is put into mistake in refrigerator while hot
White solid is precipitated in night, filters, and washes, and drying obtains 11.5 grams of crude product, yield 80.4%.Crude product fusing point m.p. be 240~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
Alcohol is put into refrigerator overnight to muddiness, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains 9.1 grams of L- selenomethionine,
Yield 82.5%.
Fusing point m.p. is 265.3 DEG C；
Specific rotatory power [ɑ]D 20=+18.3 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 2
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.9
Gram, yield 80.8%.
Fusing point m.p. is 265.7 DEG C；
Specific rotatory power [ɑ]D 20=+18.2 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1H-NMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 3
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 200mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
1h is reacted, is then cooled down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, is heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.5 grams of crude product, yield 80.4%.Fusing point m.p. is 241~242
DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 400mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.7
Gram, yield 79.0%.
Fusing point m.p. is 265.6 DEG C；Specific rotatory power [ɑ]D 20=+18.4 ° (C=0.5,1MHCl)；
Infrared IR (KBr) ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1H-NMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 4
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 200mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 3.4 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then it is cooled at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, is heated to reflux stirring
3h to 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), is filtered, filtrate is put into mistake in refrigerator while hot
White solid is precipitated in night, filters, and washes, and drying obtains 11.2 grams of crude product, yield 78.3%.Crude product fusing point m.p. be 240~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
Alcohol is put into refrigerator overnight to muddiness, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains 8.5 grams of L- selenomethionine,
Yield 77.2%.
Fusing point m.p. is 265.7 DEG C；
Specific rotatory power [ɑ]D 20=+18.2 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 5
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 6.7 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 10.9 grams of crude product, yield 76.2%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.7
Gram, yield 79.0%.
Fusing point m.p. is 265.6 DEG C；
Specific rotatory power [ɑ]D 20=+18.1 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 6
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 7.7 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 7.9 grams of crude product, yield 68.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.9
Gram, yield 80.8%.
Fusing point m.p. is 264.9 DEG C；
Specific rotatory power [ɑ]D 20=+18.2 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 7
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 40 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.2 grams of crude product, yield 78.3%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.8
Gram, yield 79.9%.
Fusing point m.p. is 265.2 DEG C；
Specific rotatory power [ɑ]D 20=+18.1 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 8
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 55 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.1 grams of crude product, yield 77.6%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.6
Gram, yield 78.1%.
Fusing point m.p. is 265.6 DEG C；
Specific rotatory power [ɑ]D 20=+18.2 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 9
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, is heated to reflux stirring
12h to 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), is filtered, filtrate is put into refrigerator while hot
Overnight, white solid is precipitated, filters, washes, drying obtains 9.2 grams of crude product, yield 64.3%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 7.9
Gram, yield 71.7%.
Fusing point m.p. is 265.3 DEG C；
Specific rotatory power [ɑ]D 20=+18.4 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 10
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 5h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 10.3 grams of crude product, yield 72.0%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.2
Gram, yield 74.5%.
Fusing point m.p. is 265.6 DEG C；
Specific rotatory power [ɑ]D 20=+18.1 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 11
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 60mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.6
Gram, yield 78.1%.
Fusing point m.p. is 265.6 DEG C；
Specific rotatory power [ɑ]D 20=+18.5 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 12
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 100mL 6.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.4
Gram, yield 76.3%.
Fusing point m.p. is 265.6 DEG C；
Specific rotatory power [ɑ]D 20=+18.4 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 13
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 4.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.7
Gram, yield 79.0%.
Fusing point m.p. is 264.8 DEG C；
Specific rotatory power [ɑ]D 20=+18.7 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 14
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 8.0mol/L is added in reaction flask together, is heated to reflux under stiring
3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine hydrolyzes completely (TLC detection), and evaporated under reduced pressure solvent is washed to free
HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, second is added dropwise
The extremely muddiness of alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.4
Gram, yield 76.3%.
Fusing point m.p. is 265.2 DEG C；
Specific rotatory power [ɑ]D 20=+18.6 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 15
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 10.0mol/L is added in reaction flask together, is heated back under stiring
It flows 3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine to hydrolyze completely (TLC detection), evaporated under reduced pressure solvent is washed to trip
From HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, be added dropwise
The extremely muddiness of ethyl alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.6
Gram, yield 78.1%.
Fusing point m.p. is 265.4 DEG C；
Specific rotatory power [ɑ]D 20=+18.1 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
Embodiment 16
L- selenomethionine is prepared using 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine:
1, the preparation method is the same as that of Example 1 for 2,5- diketopiperazine by 3,6- bis--(2- chloroethyl)-.
2, the preparation of L- selenomethionine
Blender, N are being housed2In the three-necked flask of gas-guide tube, 400mL methanol is added, 2.0 grams of metallic sodiums are dissolved to sodium
Afterwards, 4.2 grams of sodium borohydrides are added, in N2Under protection, 8.3 grams of dimethyl diselenide ethers are added dropwise, after dripping off, are stirred at 58~60 DEG C
React 1h；
Then cool down at 50 DEG C, 9.6 grams of 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine is added, be heated to reflux stirring 3h
To 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine fully reacting (TLC detection), filter while hot, filtrate is put into mistake in refrigerator
White solid is precipitated in night, filters, and washes, and drying obtains 11.0 grams of crude product, yield 76.9%.Crude product fusing point m.p. be 241~
242 DEG C, product can directly carry out the next step without purification.
By 10 grams of above-mentioned crude product, the HCl of 200mL 12.0mol/L is added in reaction flask together, is heated back under stiring
It flows 3h to 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine to hydrolyze completely (TLC detection), evaporated under reduced pressure solvent is washed to trip
From HCl completely remove, obtain a white solid, with 40mL water dissolution after, be added dropwise pyridine tune system pH5.0~6.0, be added dropwise
The extremely muddiness of ethyl alcohol, is put into refrigerator overnight, and white solid is precipitated, and filtering is recrystallized with water-ethanol, obtains L- selenomethionine 8.5
Gram, yield 77.2%.
Fusing point m.p. is 265.1 DEG C；
Specific rotatory power [ɑ]D 20=+18.7 ° (C=0.5,1MHCl)；
Infrared IR (KBr), ν/cm-1: 3300,2906,1660,1623,1580,1514,1412,1337,1274,1070；
1HNMR(D2O, 400MHz), δ (ppm): 2.00 (s, 3H, CH3Se), 2.11-2.33 (m, 2H, CH2), 2.60 (t,
2H,SeCH2)3.81(t,1H,CHCOOH)；
Electrospray ionization mass spectrum (ESI-MS), m/z:[M+1]+, measured value, 197.32, theoretical value, 197.11.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of L- selenomethionine, comprising the following steps:
A) by sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl) -2,5- diketopiperazine carries out nucleophilic substitution, obtains 3,6- bis- -
(2- first selenium ethyl) -2,5- diketopiperazine；
B) 3,6- bis--(2- first selenium ethyl) -2,5- diketopiperazine that the step A) is obtained is hydrolyzed in hydrochloric acid solution, obtained
L- selenomethionine.
2. preparation method according to claim 1, which is characterized in that the sodium methyl-hydroselenide and 3,6- bis--(2- chloroethyl)-
The molar ratio of 2,5- diketopiperazine is 1:(0.3~0.5).
3. preparation method according to claim 1, which is characterized in that the temperature of the nucleophilic substitution is 20~90
℃；
The time of the nucleophilic substitution is 3~12 hours.
4. preparation method according to claim 1, which is characterized in that the concentration of the hydrochloric acid solution is 4~12mol/L.
5. the preparation method according to claim 4, which is characterized in that 3,6-, bis--(2- first selenium ethyl) -2, the 5- diketone
The ratio between quality and the volume of hydrochloric acid solution of piperazine are 1g:(6~40) mL.
6. preparation method according to claim 1, which is characterized in that the temperature of the hydrolysis is 115~120 DEG C；
The time of the hydrolysis is 3~5 hours.
7. preparation method described in any one according to claim 1~6, which is characterized in that 3,6-, bis--(the 2- chloroethene
Base) -2,5- diketopiperazine is prepared according to the following steps to obtain:
L-Aspartic acid is esterified under the effect of the catalyst with alcohol, obtains esterification products；
The esterification products are cyclized under conditions of being heated to reflux, obtained cyclic products and reducing agent and activator are mixed
It closes, is restored, obtain 3,6- bis--(2- ethoxy) -2,5- diketopiperazine；
Obtained 3,6- bis--(2- ethoxy) -2,5- diketopiperazine is mixed with chlorinating agent, chlorination is carried out, obtains 3,6- bis- -
(2- chloroethyl) -2,5- diketopiperazine.
8. preparation method described in any one according to claim 1~6, which is characterized in that alcohol used in the esterification is
One or more of methanol, ethyl alcohol, the tert-butyl alcohol and benzylalcohol；
Catalyst used in the esterification is hydrochloric acid, sulfuric acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, thionyl chloride, strong acidic ion friendship
Change one or more of resin and lewis acid.
9. preparation method described in any one according to claim 1~6, which is characterized in that the reducing agent is sodium borohydride
And/or potassium borohydride；
The cyclic products and the molar ratio of reducing agent are 1:(4~6).
10. preparation method described in any one according to claim 1~6, which is characterized in that the chlorinating agent is phosphoric
One or more of phosphorus, phosphorus trichloride and thionyl chloride；
The temperature of the chlorination reaction is 0~40 DEG C；
The time of the chlorination reaction is 1~5 hour.
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| CN115160173A (en) * | 2022-09-01 | 2022-10-11 | 烟台海川化学制品有限公司 | N ε Process for producing dodecasyllysine |
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| WO2011112649A1 (en) * | 2010-03-09 | 2011-09-15 | Novus International Inc. | Preparation of methionine or selenomethionine from homoserine via a lactone intermediate |
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| CN110683976A (en) * | 2019-11-04 | 2020-01-14 | 济源市万洋华康生物科技有限公司 | Method for preparing (R) -selenium methyl selenocysteine |
| CN115160173A (en) * | 2022-09-01 | 2022-10-11 | 烟台海川化学制品有限公司 | N ε Process for producing dodecasyllysine |
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