CN105001108B - The preparation method of the dimethyl glutamate derivatives of optical voidness 3,4 - Google Patents
The preparation method of the dimethyl glutamate derivatives of optical voidness 3,4 Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of the dimethyl glutamate derivatives of optical voidness 3,4, the optical voidness glutamate derivatives occur asymmetric Michael reaction with cautious lattice acid esters by three epimino lactones of camphor and hydrolysis is obtained.The preparation method of optical voidness glutamate derivatives of the present invention, stereoselectivity is high, reacts obtained products collection efficiency height, and production cost is low, and the purity of product is high, and mapping percent value is high.
Description
Technical field
The present invention relates to a kind of method for preparing chiral alpha-non-natural amino acid, pass through more particularly, to one kind asymmetric
The method that Michael addition reactions prepare optical voidness 3,4- dimethyl glutamate derivatives.
Background technology
At present, the alpha-non-natural amino acid containing some unique structures in the structure of natural peptides, these amino
Acid often plays a key effect to the bioactivity of natural products.Important function of the alpha-non-natural amino acid in bioactivity causes
The strong interest of vast chemist.Compared with natural amino acid, alpha-non-natural amino acid often has unique texture, especially
It is that alpha-non-natural amino acid contains multiple asymmetric carbon atoms, such as alpha-non-natural amino acid 3,4- dimethyl glutamic acid contains three chiralitys
Center, they play extremely crucial effect in some peptides.The synthesizing mean of amino acid is increasingly becoming research ammonia
The particularly useful method of base acid structure-function relationship, for the demand of amino acid, is particularly to the amino acid of special construction
Demand is increasing, and existing amino acid kind and synthetic method far can not meet current demand.And it is existing non-
It is long that the synthetic method of natural amino acid has a synthetic route, and preparation method process is complicated, and cumbersome, stereoselectivity is low,
The yield of obtained product is relatively low, the defect that purity is not high and cost is high.
As can be seen here, the preparation synthetic method of existing alpha-non-natural amino acid has clearly disadvantageous and defect, it would be highly desirable to
It is further to improve.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of optical voidness glutamate derivatives, it has vertical
Body selectivity is high, and mapping percent value is high, and products collection efficiency is high, and product purity is high, the low advantage of production cost.
In order to solve the above technical problems, the present invention provides a kind of optical voidness 3, the preparation side of 4- dimethyl glutamate derivatives
Method, the optical voidness glutamate derivatives occur asymmetric Michael with cautious lattice acid esters by three epimino lactones of camphor and added
Into and hydrolysis obtain.
In the present invention, the optical voidness glutamate derivatives include 8 isomers of 3,4- dimethyl glutamic acid.
In the present invention, 3, the 4- dimethyl glutamic acid include (2S, 3S, 4R) -3,4- dimethyl glutamic acid, (2S, 3R,
4R) -3,4- dimethyl glutamic acid, (2S, 3R, 4S) -3,4- dimethyl glutamic acid, (2S, 3S, 4S) -3,4- dimethyl glutamic acid,
(2R, 3R, 4R) -3,4- dimethyl glutamic acid, (2R, 3S, 4R) -3,4- dimethyl glutamic acid, (2R, 3S, 4S) -3,4- dimethyl
Glutamic acid, (2R, 3R, 4S) -3,4- dimethyl 8 kinds of isomers of glutamic acid.
In the present invention, the cautious lattice acid esters includes the sour fourth of cautious lattice acetoacetic ester, cautious lattice propyl propionate, cautious lattice isopropyl propionate, cautious lattice
Ester, cautious lattice tert-butyl acrylate, cautious lattice acid benzyl ester, cautious lattice acid 2,6- dibromos benzyl ester, cautious lattice acid 2,6- dichloros benzyl ester, cautious lattice acid 2,6- bis-
The sour trifluoro ethyl ester of fluoro-methylbenzyl ester, cautious lattice acid 2- p-Nitrobenzyls, cautious lattice acid 2,6- dinitros benzyl ester, cautious lattice.
In the present invention, described (2R, 3S, 4R) -3,4- dimethyl glutamic acid preparation methods are specific as follows：
Step 1：2,6- benzyl dichlorides bromine, cautious lattice acid, potassium carbonate and acetonitrile are added to the single port bottle with reflux condensing tube
In, wherein, 2,6- benzyl dichloride bromines, cautious lattice acid, the mol ratio of potassium carbonate are 1.0:1.4:1.4, reaction is cooled to room after 4-6 hours
Temperature, concentration and recovery solvent adds 20-40 milliliters of water, through extracting, being dried to obtain the cautious lattice acid 2 with chemical formula 7,6- benzyl dichlorides
Ester；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and diisopropylamine are inserted in reactor, -30 DEG C are cooled to -- 45 DEG C
Afterwards, the tetrahydrofuran solution of three epimino lactones with chemical formula 1, equimolar highly basic are added and with chemical formula 7
Cautious lattice acid 2, the tetrahydrofuran solution of 6- dichloro benzyl esters reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched with saturated ammonium chloride, passes through
Be concentrated under reduced pressure recovery tetrahydrofuran, wherein, anhydrous Lithium chloride and diisopropylamine and three epimino lactones and cautious lattice acid 2,6- dichloros
The molar ratio of benzyl ester is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：A certain amount of water will be added in product in step 2, had by extraction, washing, dry be concentrated to give
The mixture of the compound of chemical formula 8 and compound with chemical formula 9；
Step 4：The mixture obtained in step 3 is separated by recrystallizing, the compound with chemical formula 8 is respectively obtained
With the compound with chemical formula 9；
Step 5：Compound with chemical formula 8 is dissolved in 4-6N hydrochloric acid, 70-90 DEG C is heated to, after stirring 3-5 hours
It is cooled to room temperature；
Step 6：By the product in step 5 through corresponding oxyphor is obtained by extraction, remove under reduced pressure and volume is added after hydrochloric acid
Than for 1:1 absolute ethyl alcohol and expoxy propane, backflow obtains solid matter, and (2R, 3S, 4R) -3,4- diformazans are obtained after filtering
Base glutamic acid.
In the present invention, (2R, 3R, 4S) -3,4- dimethyl glutamic acid preparation method is specific as follows：
Step 1：2,6- benzyl dichlorides bromine, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and reacted, reaction
Room temperature is cooled to after 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, through extracting, being dried to obtain with chemical formula 7
Cautious lattice acid 2,6- dichloro benzyl esters；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and highly basic are inserted in reactor, -30 DEG C are cooled to -- after 45 DEG C,
Add the tetrahydrofuran solution of the three epimino lactones with chemical formula 1 and the cautious lattice acid 2,6- dichloro benzyl esters with chemical formula 7
Tetrahydrofuran solution, in -5 DEG C -5 DEG C react 25-35 hour, be quenched with saturated ammonium chloride, through be concentrated under reduced pressure recovery tetrahydrochysene furan
Mutter, wherein, anhydrous Lithium chloride, diisopropylamine and the three epimino lactones with chemical formula 1 and cautious lattice acid 2,6- dichloro benzyl esters
Molar ratio is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：Product in step 2 is added into a certain amount of water, there is chemistry through extraction, washing, dry be concentrated to give
The compound of formula 8 and the mixture with chemistry 9；
Step 4：By the mixture in step 3 by recrystallize separate, respectively obtain with chemical formula for 8 compound and
With the compound that chemical formula is 9；
Step 5：It will be dissolved in chemical formula for 9 compound in 4-6N hydrochloric acid, be heated to 70-90 DEG C, stir 3-5 hours
After be cooled to room temperature；
Step 6：Corresponding oxyphor is obtained by extraction in the product obtained in step 5, removes under reduced pressure and body is added after hydrochloric acid
Product is than being 1:1 absolute ethyl alcohol and expoxy propane mixed liquor, backflow obtains obtaining (2R, 3R, 4S) -3 after solid matter, filtering,
4- dimethyl glutamic acid.
In the present invention, the preparation method of (2S, 3S, 4R) -3,4- dimethyl glutamic acid is specific as follows：
Step 1：2,6- benzyl dichlorides bromine, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and mixed, reaction
Room temperature is cooled to after 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, by extracting, being dried to obtain with chemical formula 7
Cautious lattice acid 2,6- dichloro benzyl esters；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and diisopropylamine are inserted in reactor, -30 DEG C are cooled to -- 45 DEG C
Afterwards, the tetrahydrofuran solution of three epimino lactones with chemical formula 2, equimolar highly basic are added and with chemical formula 7
Cautious lattice acid 2, the tetrahydrofuran solution of 6- dichloro benzyl esters reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched, subtracted with saturated ammonium chloride
Concentration and recovery tetrahydrofuran is pressed, wherein, anhydrous Lithium chloride, diisopropylamine and the three epimino lactones with chemical formula 2 and cautious lattice
The molar ratio of sour 2,6- dichloros benzyl ester is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：Product in step 2 is added into a certain amount of water, there is chemistry through extraction, washing, dry be concentrated to give
The mixture of the compound of formula 10 and compound with chemical formula 11；
Step 4：Mixture in step 3 is separated by recrystallizing, respectively obtain compound with chemical formula 10 and
With the compound that chemical formula is 11；
Step 5：It will be dissolved in chemical formula for 10 compound in 4-6N hydrochloric acid, be heated to 70-90 DEG C, stirring 3-5 is small
When after be cooled to room temperature；
Step 6：By reaction product in step 5 through corresponding oxyphor is obtained by extraction, remove under reduced pressure and body is added after hydrochloric acid
Product is than being 1:1 absolute ethyl alcohol and expoxy propane mixed liquor, backflow obtain solid matter, obtained after filter product (2S, 3S,
4R) -3,4- dimethyl glutamic acid.
In the present invention, described highly basic includes n-BuLi, tert-butyl lithium, isobutyl group lithium, phenyl lithium, diisopropyl ammonia
Lithium, hexamethl disilamine lithium, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide.
Beneficial effects of the present invention：
The preparation method of optical voidness glutamate derivatives of the present invention, preparation method stereoselectivity height, obtained product
Yield is high, production cost is low, purity is high, and mapping percent value is high.
Embodiment
The present invention will the invention will be further described by embodiment, and these descriptions are not to enter one to present invention
The restriction of step.Person skilled should be understood that the equivalent substitution made to the technical characteristic of the present invention, or be correspondingly improved,
Belong to protection scope of the present invention.
The preparation method of optical voidness glutamate derivatives of the present invention is that the three epimino lactones based on camphor are template, and cautious
Asymmetric Michael reaction and hydrolysis occur for lattice acid esters, and High level of stereoselectivity optionally synthesizes 3,4- dimethyl glutamic acid
Process.
Wherein, the present invention refers to figure below using the asymmetric syntheses that three epimino lactones of camphor are template, and three rings are sub-
Amine lactone includes the three epimino lactones with chemical formula 1 and the three epimino lactones with chemical formula 2.
Cautious lattice acid esters is alpha, beta-unsaturated esters, and it includes cautious lattice acetoacetic ester, cautious lattice propyl propionate, cautious lattice isopropyl propionate, cautious lattice
Acid butyl ester, cautious lattice tert-butyl acrylate, cautious lattice acid benzyl ester, cautious lattice acid 2,6- dibromos benzyl ester, cautious lattice acid 2,6- dichloros benzyl ester, cautious lattice acid 2,
The fluoro-methylbenzyl esters of 6- bis-, cautious lattice acid 2- p-Nitrobenzyls, cautious lattice acid 2,6- dinitro benzyl esters.Preferably, the sour trifluoro ethyl ester of cautious lattice, cautious lattice acid
2,6- dichloro benzyl esters, cautious lattice acid 2, the fluoro-methylbenzyl esters of 6- bis-, cautious lattice acid 2,6- dinitros benzyl ester have compared with high reaction activity, especially cautious
Lattice acid 2,6- dibromos benzyl ester, cautious lattice acid 2,6- dichloros benzyl ester, cautious lattice acid 2,6- bis- fluoro-methylbenzyl esters have higher stereoselectivity.
The alkali used in the present invention is：N-BuLi, tert-butyl lithium, isobutyl group lithium, phenyl lithium, diisopropyl ammonia lithium, six
The silicon ammonia lithium of methyl two, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide.
In the present invention, 3,4- dimethyl glutamic acid include (2S, 3S, 4R) -3,4- dimethyl glutamic acid, (2S, 3R, 4R) -
3,4- dimethyl glutamic acid, (2S, 3R, 4S) -3,4- dimethyl glutamic acid, (2S, 3S, 4S) -3,4- dimethyl glutamic acid, (2R,
3R, 4R) -3,4- dimethyl glutamic acid, (2R, 3S, 4R) -3,4- dimethyl glutamic acid, (2R, 3S, 4S) -3,4- dimethyl paddy ammonia
Acid, (2R, 3R, 4S) -3,4- dimethyl 8 kinds of isomers of glutamic acid.
Now by specific embodiment, the specific preparation side of the optical voidness glutamate derivatives of the present invention is further illustrated
Method.
The synthesis of example 1 (2R, 3S, 4R) -3,4- dimethyl glutamic acid
In the present embodiment, the preparation method of (2R, 3S, 4R) -3,4- dimethyl glutamic acid is specific as follows：
Step 1：Cautious lattice acid 2,6- dichloro benzyl ester of the synthesis with chemical formula 7.
By 2.4 grams of (10mmol) 2,6- benzyl dichloride bromines, 1.4 grams (1.4eq) cautious lattice acid, 1.9 grams of (14mmol) potassium carbonate and
40 milliliters of acetonitriles are added in the single port bottle with reflux condensing tube, preferably, 2,6- benzyl dichloride bromines, cautious lattice are sour, potassium carbonate
Mol ratio is 1.0:1.4:1.4, back flow reaction is cooled to room temperature in 4-6 hours after (preferably reacting 5 hours), removes under reduced pressure molten
Agent, adds 20-40 milliliters of water (preferably 30 milliliters water), and ethyl acetate extraction (15mL × 3), anhydrous magnesium sulfate is dried, concentration
Obtain 2.5 grams of colourless oil liquids, the compound with chemical formula 7, yield 98%.This has the compound of chemical formula 71H
NMR spectra analysis result is as follows：
1H NMR(500MHz,CDCl3)δ:7.34 (d, J=8.0Hz, 2H), 7.21-7.26 (m, 1H), 6.83-6.87 (m,
1H), 5.43 (s, 2H), 1.83 (d, J=1.0Hz, 3H), 1.76 (dd, J=7.5,1.0Hz, 3H)；13C NMR(125MHz,
CDCl3)δ:167.9,137.9,137.1,131.9,130.5,128.6,128.5,128.4,61.5,14.5,12.2。
Step 2：By anhydrous Lithium chloride (425mg, 10mmol), 10 milliliters of tetrahydrofurans and 385 microlitres of (1.1eq) diisopropyls
Amine is placed in reactor, after -45 DEG C of -30- (preferably, reaction temperature is -40 DEG C) is cooled to, is separately added into diisopropyl ammonia lithium
(2.4M, 1.1eq), 10 milliliters dissolved with 520 milligrams have chemical formula 1 three epimino lactones tetrahydrofuran solution and 10 milliliters
Dissolved with the tetrahydrofuran solution of the acid 2,6- dichloro benzyl esters of the cautious lattice with chemical formula 7 of 777 milligrams (1.2eq).(or add tool
There are the tetrahydrofuran solution, equimolar highly basic and the cautious lattice acid 2,6- with chemical formula 7 of three epimino lactones of chemical formula 1
The tetrahydrofuran solution of dichloro benzyl ester, the highly basic includes n-BuLi, tert-butyl lithium, isobutyl group lithium, phenyl lithium, diisopropyl ammonia
Lithium, hexamethl disilamine lithium, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide etc.) in -5 DEG C -5 DEG C (preferably, anti-temperature is 0 DEG C)
Under the conditions of after reaction 25-35 hour (preferably, react 30 hours), be quenched with 1 milliliter of saturated ammonium chloride, be concentrated under reduced pressure recovery four
Hydrogen furans.Preferably, anhydrous Lithium chloride and diisopropylamine and three epimino lactones and cautious lattice acid 2, the mol ratio of 6- dichloro benzyl esters
Example is (2.0~8.0):(1.0~1.2):1:(1.0~1.3)；
Step 3：10 milliliters of water will be added in residue in step 2, (5mL × 3), saturated common salt are extracted with ethyl acetate
Water washing organic phase, dries, is concentrated to give crude product.Column chromatography (petroleum ether:Ethyl acetate=8:1) separate, obtain white solid,
It is the mixture with the compound of chemical formula 8 and the compound of chemical formula 9, the yield 81% of product.
Step 4：By the mixture in step 3 using ethyl acetate/n-hexane mixed solvent as recrystallization solvent, by tying again
Crystalline substance separation.The crystallization of precipitation is that, with the compound of chemical formula 8, will be dissolved in containing the compound with chemical formula 9 in mother liquor, weight
Crystalline mother solution is concentrated, and a small amount of ethyl acetate is added in obtained solids, is recrystallized to give the chemical combination with chemical formula 9
Thing.Wherein, the fusing point of the compound with chemical formula 8 is mp:170–172℃；Its specific rotation rate is：[α]D 20=+113.7 (c
=0.50, CHCl3)。
Compound with chemical formula 81HNMR pattern analysis results are as follows：
1H NMR(500MHz,CDCl3)δ:7.35 (d, J=8.0Hz, 2H), 7.22-7.24 (m, 1H), 5.38 (dd, J=
32.5,11.5Hz, 2H), 4.39 (d, J=1.5Hz, 1H), 3.89 (dd, J=3.5,1.5Hz, 1H), 2.87-2.94 (m, 1H),
2.59-2.65 (m, 1H), 2.22 (d, J=4.5Hz, 1H), 2.03-2.10 (m, 1H), 1.72-1.78 (m, 1H), 1.56-1.59
(m, 1H), 1.31-1.36 (m, 1H), 1.22 (d, J=7.0Hz, 3H), 1.01 (d, J=5.0Hz, 3H), 1.00 (s, 3H),
0.95(s,3H),0.72(s,3H)；13C NMR(125MHz,CDCl3)δ:181.9,175.8,170.5,137.0,131.6,
130.5,128.4,79.2,61.2,61.1,52.7,48.8,47.5,42.6,37.0,29.4,25.4,20.0,19.6,15.6,
13.2,9.9。
The fusing point of compound with chemical formula 9 is mp:178–179℃；[α] of compound with chemical formula 9D 20=+
152.8 (c=0.36, CHCl3)。
Compound with chemical formula 91HNMR pattern analysis results are as follows：
1H NMR(500MHz,CDCl3)δ:7.33-7.35 (m, 2H), 7.22-7.26 (m, 1H), 5..36 (d, J=
5.0Hz, 2H), 4.32 (d, J=1.5Hz, 1H), 3.68 (dd, J=7.0,1.5Hz, 1H), 3.26-3.32 (m, 1H), 2.56-
2.63 (m, 1H), 2.22 (d, J=5.0Hz, 1H), 2.01-2.08 (m, 1H), 1.68-1.74 (m, 1H), 1.38-1.44 (m,
1H), 1.24-1.28 (m, 1H), 1.22 (d, J=7.0Hz, 3H), 1.16 (d, J=7.0Hz, 3H), 1.00 (s, 3H), 0.94
(s,3H),0.74(s,3H)；13C NMR(125MHz,CDCl3)δ:182.7,175.4,170.3,136.9,131.8,130.4,
128.4,79.4,63.3,61.0,52.4,49.1,47.3,40.7,37.7,29.5,25.3,20.1,19.7,15.2,14.6,
9.8。
Step 5：By the Michael addition compound products of 3 mmoles, the compound with chemical formula 8 is dissolved in 3 milliliters of 6N hydrochloric acid,
It is heated to 70-90 DEG C (preferably, being heated to 85 DEG C), stirring is cooled to room temperature in 3-5 hours after (preferably, stirring 4 hours).
Step 6：Product in step 5 is extracted into (2mL × 3) by ether, is evaporated off obtaining corresponding oxyphor after ether.
Removing 2 milliliters of absolute ethyl alcohols of addition and 2 milliliters of expoxy propane after hydrochloric acid under reduced pressure, (volume ratio of absolute ethyl alcohol and expoxy propane is 1:
1) white solid is produced after, flowing back 30 minutes, (2R, 3S, 4R) -3,4- dimethyl glutamic acid is filtered.
It is somebody's turn to do (2R, 3S, 4R) -3,4- dimethyl glutamic acid1HNMR pattern analysis results are as follows：
1H NMR(500MHz,D2O)δ:4.14 (d, J=4.0Hz, 1H), 2.58-2.64 (m, 1H), 2.43-2.47 (m,
1H), 1.26 (d, J=7.0Hz, 3H), 1.00 (d, J=7.5Hz, 3H)；13C NMR(125MHz,D2O)δ:179.3,172.4,
55.5,42.1,36.8,14.9,11.3。
The synthesis of example 2 (2R, 3S, 4R) -3,4- dimethyl glutamic acid
Step 1：Cautious lattice acid 2,6- dichloro benzyl ester of the synthesis with chemical formula 7.
By 2.4 grams of (10mmol) 2,6- benzyl dichloride bromines, 1.4 grams (1.4eq) cautious lattice acid, 1.9 grams of (14mmol) potassium carbonate and
40 milliliters of acetonitriles are added in the single port bottle with reflux condensing tube, and back flow reaction is cooled to room temperature after 6 hours, are removed under reduced pressure molten
Agent, adds 40 milliliters of water, and ethyl acetate extraction (15mL × 3), anhydrous magnesium sulfate is dried, and is concentrated to give 2.5 grams of colorless oil liquid
Body, the compound with chemical formula 7, yield 98%.This has the compound of chemical formula 71H NMR spectras analysis result is such as
Under：
1H NMR(500MHz,CDCl3)δ:7.34 (d, J=8.0Hz, 2H), 7.21-7.26 (m, 1H), 6.83-6.87 (m,
1H), 5.43 (s, 2H), 1.83 (d, J=1.0Hz, 3H), 1.76 (dd, J=7.5,1.0Hz, 3H)；13C NMR(125MHz,
CDCl3)δ:167.9,137.9,137.1,131.9,130.5,128.6,128.5,128.4,61.5,14.5,12.2。
Step 2：By anhydrous Lithium chloride (425mg, 10mmol), 10 milliliters of tetrahydrofurans and 385 microlitres of (1.1eq) diisopropyls
Amine is placed in reactor, after -45 DEG C of -45 DEG C of -30- (preferably, reaction temperature is -40 DEG C) is cooled to, is separately added into 1.14 millis
Rise n-BuLi (2.4M, 1.1eq), 10 milliliters of tetrahydrofurans dissolved with 520 milligrams of three epimino lactones with chemical formula 1 molten
Liquid and 10 milliliters of tetrahydrofuran solutions dissolved with the acid 2,6- dichloro benzyl esters of the cautious lattice with chemical formula 7 of 777 milligrams (1.2eq).
After being reacted 35 hours under the conditions of -5 DEG C, it is quenched with 1 milliliter of saturated ammonium chloride, be concentrated under reduced pressure recovery tetrahydrofuran.
Step 3：10 milliliters of water will be added in residue in step 2, (5mL × 3), saturated common salt are extracted with ethyl acetate
Water washing organic phase, dries, is concentrated to give crude product.Column chromatography (petroleum ether:Ethyl acetate=8:1) separate, obtain white solid,
It is compound and the mixture of the compound of chemical formula 9 with chemical formula 8, the yield 79% of product.
Step 4：By the mixture in step 3 using ethyl acetate/n-hexane mixed solvent as recrystallization solvent, by tying again
Crystalline substance separation.The crystallization of precipitation is that, with the compound of chemical formula 8, will be dissolved in containing the compound with chemical formula 9 in mother liquor, weight
Crystalline mother solution is concentrated, and a small amount of ethyl acetate is added in obtained solids, is recrystallized to give the chemical combination with chemical formula 9
Thing.
Wherein, the fusing point of the compound with chemical formula 8 is mp:170–172℃；Its specific rotation rate is：[α]D 20=+
113.7 (c=0.50, CHCl3)。
Compound with chemical formula 81HNMR pattern analysis results are as follows：
1H NMR(500MHz,CDCl3)δ:7.35 (d, J=8.0Hz, 2H), 7.22-7.24 (m, 1H), 5.38 (dd, J=
32.5,11.5Hz, 2H), 4.39 (d, J=1.5Hz, 1H), 3.89 (dd, J=3.5,1.5Hz, 1H), 2.87-2.94 (m, 1H),
2.59-2.65 (m, 1H), 2.22 (d, J=4.5Hz, 1H), 2.03-2.10 (m, 1H), 1.72-1.78 (m, 1H), 1.56-1.59
(m, 1H), 1.31-1.36 (m, 1H), 1.22 (d, J=7.0Hz, 3H), 1.01 (d, J=5.0Hz, 3H), 1.00 (s, 3H),
0.95(s,3H),0.72(s,3H)；13C NMR(125MHz,CDCl3)δ:181.9,175.8,170.5,137.0,131.6,
130.5,128.4,79.2,61.2,61.1,52.7,48.8,47.5,42.6,37.0,29.4,25.4,20.0,19.6,15.6,
13.2,9.9。
The fusing point of compound with chemical formula 9 is mp:178–179℃；[α] of compound with chemical formula 9D 20=+
152.8 (c=0.36, CHCl3)。
Compound with chemical formula 91HNMR pattern analysis results are as follows：
1H NMR(500MHz,CDCl3)δ:7.33-7.35 (m, 2H), 7.22-7.26 (m, 1H), 5..36 (d, J=
5.0Hz, 2H), 4.32 (d, J=1.5Hz, 1H), 3.68 (dd, J=7.0,1.5Hz, 1H), 3.26-3.32 (m, 1H), 2.56-
2.63 (m, 1H), 2.22 (d, J=5.0Hz, 1H), 2.01-2.08 (m, 1H), 1.68-1.74 (m, 1H), 1.38-1.44 (m,
1H), 1.24-1.28 (m, 1H), 1.22 (d, J=7.0Hz, 3H), 1.16 (d, J=7.0Hz, 3H), 1.00 (s, 3H), 0.94
(s,3H),0.74(s,3H)；13C NMR(125MHz,CDCl3)δ:182.7,175.4,170.3,136.9,131.8,130.4,
128.4,79.4,63.3,61.0,52.4,49.1,47.3,40.7,37.7,29.5,25.3,20.1,19.7,15.2,14.6,
9.8。
Step 5：By the Michael addition compound products of 3 mmoles, the compound with chemical formula 8 is dissolved in 3 milliliters of 4N hydrochloric acid,
80 DEG C are heated to, stirring is cooled to room temperature after 5 hours.
Step 6：Product in step 5 is extracted into (2mL × 3) by ether, is evaporated off obtaining corresponding oxyphor after ether.
Removing 2 milliliters of absolute ethyl alcohols of addition and 2 milliliters of expoxy propane after hydrochloric acid under reduced pressure, (volume ratio is 1:1 absolute ethyl alcohol and epoxy third
Alkane mixed liquor), backflow produces white solid after 30 minutes, filters (2R, 3S, 4R) -3,4- dimethyl glutamic acid.
It is somebody's turn to do (2R, 3S, 4R) -3,4- dimethyl glutamic acid1HNMR pattern analysis results are as follows：
1H NMR(500MHz,D2O)δ:4.14 (d, J=4.0Hz, 1H), 2.58-2.64 (m, 1H), 2.43-2.47 (m,
1H), 1.26 (d, J=7.0Hz, 3H), 1.00 (d, J=7.5Hz, 3H)；13CNMR(125MHz,D2O)δ:179.3,172.4,
55.5,42.1,36.8,14.9,11.3。
The synthesis of example 3 (2R, 3R, 4S) -3,4- dimethyl glutamic acid
(2R, 3R, 4S) -3,4- dimethyl glutamic acid preparation methods are specific as follows：
Step 1：2,6- benzyl dichlorides bromine, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and reacted, reaction
Room temperature is cooled to after 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, through extracting, being dried to obtain cautious lattice acid 2,6- bis-
Benzyl chloride ester；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and highly basic are inserted in reactor, -30 DEG C are cooled to -- after 45 DEG C,
Add the tetrahydrofuran solution of the three epimino lactones with chemical formula 1 and the cautious lattice acid 2,6- dichloro benzyl esters with chemical formula 7
Tetrahydrofuran solution, in -5 DEG C -5 DEG C react 25-35 hour, be quenched with saturated ammonium chloride, through be concentrated under reduced pressure recovery tetrahydrochysene furan
Mutter.Preferably, anhydrous Lithium chloride and diisopropylamine and three epimino lactones and cautious lattice acid 2, the molar ratio of 6- dichloro benzyl esters is
(2.0~8.0):(1.0~1.2):1:(1.0~1.3)；Wherein, highly basic includes n-BuLi, tert-butyl lithium, isobutyl group lithium, benzene
Base lithium, diisopropyl ammonia lithium, hexamethl disilamine lithium, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide；
Step 3：Product in step 2 is added into a certain amount of water, there is chemistry through extraction, washing, dry be concentrated to give
The compound of formula 8 and the mixture with chemistry 9；
Step 4：By the mixture in step 3 by recrystallize separate, respectively obtain with chemical formula for 8 compound and
With the compound that chemical formula is 9；
Step 5：It will be dissolved in chemical formula for 9 compound in 4-6N hydrochloric acid, be heated to 70-90 DEG C, stir 3-5 hours
After be cooled to room temperature；
Step 6：Corresponding oxyphor is obtained by extraction in the product obtained in step 5, removes under reduced pressure and body is added after hydrochloric acid
Product is than being 1:1 absolute ethyl alcohol and expoxy propane, backflow obtains obtaining (2R, 3R, 4S) -3,4- diformazans after solid matter, filtering
Base glutamic acid.
In the present embodiment, with Michael addition compound products there is the compound of chemical formula 9 to replace the Michael in example 2 to add
There is the compound of chemical formula 8 into product, other courses of reaction are identical with the preparation process of example 2, and target can be finally made
Product (2R, 3R, 4S) -3,4- dimethyl glutamic acid.
It is somebody's turn to do (2R, 3R, 4S) -3,4- dimethyl glutamic acid1H NMR spectra analysis results are as follows：
1H NMR(500MHz,D2O)δ:4.33 (d, J=7.0Hz, 1H), 2.80-2.85 (m, 1H), 2.59-2.66 (m,
1H), 0.93 (d, J=7.0Hz, 3H), 0.78 (d, J=7.5Hz, 3H)；13C NMR(125MHz,D2O)δ:175.1,172.4,
59.5,40.4,35.0,143.8,9.7。
The synthesis of example 4 (2S, 3S, 4R) -3,4- dimethyl glutamic acid and (2S, 3R, 4R) -3,4- dimethyl glutamic acid
The preparation method of (2S, 3S, 4R) -3,4- dimethyl glutamic acid is specific as follows：
Step 1：2,6- benzyl dichlorides bromine, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and mixed, reaction
Room temperature is cooled to after 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, by extracting, being dried to obtain with chemical formula 7
Cautious lattice acid 2,6- dichloro benzyl esters；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and diisopropylamine are inserted in reactor, -30 DEG C are cooled to -- 45 DEG C
Afterwards, the tetrahydrofuran solution of three epimino lactones with chemical formula 2, equimolar highly basic are added and with chemical formula 7
Cautious lattice acid 2, the tetrahydrofuran solution of 6- dichloro benzyl esters reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched, subtracted with saturated ammonium chloride
Concentration and recovery tetrahydrofuran is pressed, preferably, anhydrous Lithium chloride and diisopropylamine and three epimino lactones and cautious lattice acid 2,6- dichloros
The molar ratio of benzyl ester is (2.0~8.0):(1.0~1.2):1:(1.0~1.3), wherein, highly basic includes n-BuLi, tertiary fourth
Base lithium, isobutyl group lithium, phenyl lithium, diisopropyl ammonia lithium, hexamethl disilamine lithium, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide；
Step 3：Product in step 2 is added into a certain amount of water, there is chemistry through extraction, washing, dry be concentrated to give
The mixture of the compound of formula 10 and compound with chemical formula 11；
Step 4：Mixture in step 3 is separated by recrystallizing, respectively obtain compound with chemical formula 10 and
With the compound that chemical formula is 11；
Step 5：It will be dissolved in chemical formula for 10 compound in 4-6N hydrochloric acid, be heated to 70-90 DEG C, stirring 3-5 is small
When after be cooled to room temperature；
Step 6：By reaction product in step 5 through corresponding oxyphor is obtained by extraction, remove under reduced pressure and body is added after hydrochloric acid
Product is than being 1:1 absolute ethyl alcohol and expoxy propane mixed solution, backflow obtain solid matter, obtained after filter product (2S, 3S,
4R) -3,4- dimethyl glutamic acid.
In the present embodiment, three with chemical formula 1 in example 1 are replaced using the three epimino lactones with chemical formula 2
Epimino lactone, replaces the diisopropyl ammonia lithium in example 1 with hexamethl disilamine lithium, can finally prepare with chemical formula 10
Compound and the compound with chemical formula 11, further hydrolysis has the compound of chemical formula 10 and with chemical formula respectively
11, respectively obtain (2S, 3S, 4R) -3,4- dimethyl glutamic acid and (2S, 3R, 4S) -3,4- dimethyl glutamic acid.
Coordinate refering to embodiment 1 to the preparation method of embodiment 4, can equally prepare (2S, 3S, 4S) -3,4- diformazans
Base glutamic acid, (2R, 3R, 4R) -3,4- dimethyl glutamic acid and (2R, 3S, 4S) -3,4- dimethyl glutamic acid.
The preparation method of the optical voidness glutamate derivatives of the present invention, its stereoselectivity is high, and mapping percentage ee% is big
In 99%；Diastereomer separation is more than 99% using recrystallization, its mapping percentage ee%；The preparation method of the present invention,
Production cost is low, and yield is high, and operating process is simple.
Presently preferred embodiments of the present invention is these are only, this is not able to and limits the protection domain that the present invention is implemented, therefore all ginsengs
The simple equivalent changes and modifications that the description of the present invention is made is examined, still belongs to protection scope of the present invention.
Claims (4)
1. a kind of optical voidness 3, the preparation method of 4- dimethyl glutamate derivatives, it is characterised in that
The optical voidness glutamate derivatives occur asymmetric Michael with cautious lattice acid esters by three epimino lactones of camphor and added
Into and hydrolysis obtain；
The optical voidness glutamate derivatives are following 8 isomers：
(2S, 3S, 4R) -3,4- dimethyl glutamic acid, (2S, 3R, 4R) -3,4- dimethyl glutamic acid, (2S, 3R, 4S) -3,4- two
Methyl glutamic acid, (2S, 3S, 4S) -3,4- dimethyl glutamic acid, (2R, 3R, 4R) -3,4- dimethyl glutamic acid, (2R, 3S,
4R) -3,4- dimethyl glutamic acid, (2R, 3S, 4S) -3,4- dimethyl glutamic acid, (2R, 3R, 4S) -3,4- dimethyl glutamic acid；
The cautious lattice acid esters be cautious lattice acetoacetic ester, cautious lattice propyl propionate, cautious lattice isopropyl propionate, cautious lattice acid butyl ester, cautious lattice tert-butyl acrylate,
Cautious lattice acid benzyl ester, cautious lattice acid 2,6- dibromos benzyl ester, cautious lattice acid 2,6- dichloros benzyl ester, cautious lattice acid 2,6- bis- fluoro-methylbenzyl esters, cautious lattice acid 2-
The sour trifluoro ethyl ester of p-Nitrobenzyl, cautious lattice acid 2,6- dinitros benzyl ester, cautious lattice；
The preparation method of above-mentioned eight isomers is as follows：
Wherein, R=ethyls, propyl group, isopropyl, normal-butyl, the tert-butyl group, benzyl, 2,6- dibromo-benzyls, 2,6- dichloro benzyls, 2,
6- difluorobenzyls, 2- nitrobenzyls, 2,6- dinitrobenzyls, trifluoroethyl；
Described highly basic includes n-BuLi, tert-butyl lithium, isobutyl group lithium, phenyl lithium, diisopropyl ammonia lithium, hexamethl disilamine
Lithium, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide.
2. optical voidness 3 as claimed in claim 1, the preparation method of 4- dimethyl glutamate derivatives, it is characterised in that：It is described
(2R, 3S, 4R) -3,4- dimethyl glutamic acid preparation methods it is specific as follows：
Step 1：2,6- benzyl dichlorides bromine, cautious lattice acid, potassium carbonate and acetonitrile are added in the single port bottle with reflux condensing tube, its
In, 2,6- benzyl dichloride bromines, cautious lattice acid, the mol ratio of potassium carbonate are 1.0:1.4:1.4, reaction is cooled to room temperature after 4-6 hours, dense
Contracting recycling design, adds 20-40 milliliters of water, through extracting, being dried to obtain the cautious lattice acid 2 with chemical formula 7,6- dichloro benzyl esters；Step
Rapid 2：Anhydrous Lithium chloride, tetrahydrofuran and diisopropylamine are inserted in reactor, -30 DEG C are cooled to -- after 45 DEG C, add tool
There are the tetrahydrofuran solution, equimolar highly basic and the cautious lattice acid 2,6- with chemical formula 7 of three epimino lactones of chemical formula 1
The tetrahydrofuran solution of dichloro benzyl ester, reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched with saturated ammonium chloride, through being concentrated under reduced pressure back
Tetrahydrofuran is received, wherein, anhydrous Lithium chloride and diisopropylamine and three epimino lactones and cautious lattice acid 2, mole of 6- dichloro benzyl esters
Ratio is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：A certain amount of water will be added in product in step 2, there is chemistry by extraction, washing, dry be concentrated to give
The mixture of the compound of formula 8 and compound with chemical formula 9；
Step 4：The mixture obtained in step 3 is separated by recrystallizing, compound and tool with chemical formula 8 is respectively obtained
There is the compound of chemical formula 9；
Step 5：Compound with chemical formula 8 is dissolved in 4-6N hydrochloric acid, 70-90 DEG C is heated to, stirring is cooled down after 3-5 hours
To room temperature；
Step 6：By the product in step 5 through corresponding oxyphor is obtained by extraction, removing addition volume ratio after hydrochloric acid under reduced pressure is
1:1 absolute ethyl alcohol and expoxy propane, backflow obtains solid matter, and (2R, 3S, 4R) -3,4- dimethyl paddy is obtained after filtering
Propylhomoserin.
3. optical voidness 3 as claimed in claim 1, the preparation method of 4- dimethyl glutamate derivatives, it is characterised in that
(2R, 3R, the 4S) -3,4- dimethyl glutamic acid preparation methods are specific as follows：
Step 1：2,6- benzyl dichlorides bromine, cautious lattice acid, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and reacted, instead
Room temperature is cooled to after answering 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, through extracting, being dried to obtain with chemical formula 7
Cautious lattice acid 2,6- dichloro benzyl esters；
Step 2：Anhydrous Lithium chloride, diisopropylamine, tetrahydrofuran and highly basic are inserted in reactor, -30 DEG C are cooled to -- 45
After DEG C, the tetrahydrofuran solution of the three epimino lactones with chemical formula 1 and the cautious lattice acid 2 with chemical formula 7,6- dichloros are added
The tetrahydrofuran solution of benzyl ester, reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched with saturated ammonium chloride, through the recovery four that is concentrated under reduced pressure
Hydrogen furans, wherein, anhydrous Lithium chloride, diisopropylamine and the three epimino lactones with chemical formula 1 and cautious lattice acid 2,6- benzyl dichlorides
The molar ratio of ester is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：Product in step 2 is added into a certain amount of water, is concentrated to give through extraction, washing, drying with chemical formula 8
Compound and the mixture with chemistry 9；
Step 4：Mixture in step 3 is separated by recrystallizing, respectively obtains with the compound that chemical formula is 8 and has
Chemical formula is 9 compound；
Step 5：It will be dissolved in chemical formula for 9 compound in 4-6N hydrochloric acid, and be heated to 70-90 DEG C, it is cold after stirring 3-5 hours
But to room temperature；
Step 6：Corresponding oxyphor is obtained by extraction in the product obtained in step 5, removes under reduced pressure and volume ratio is added after hydrochloric acid
For 1:1 absolute ethyl alcohol and expoxy propane mixed liquor, backflow obtains obtaining (2R, 3R, 4S) -3,4- bis- after solid matter, filtering
Methyl glutamic acid.
4. optical voidness 3 as claimed in claim 1, the preparation method of 4- dimethyl glutamate derivatives, it is characterised in that
The preparation method of (2S, 3S, the 4R) -3,4- dimethyl glutamic acid is specific as follows：
Step 1：2,6- benzyl dichlorides bromine, cautious lattice acid, potassium carbonate and acetonitrile are added in the single port bottle of reflux condensing tube and mixed, instead
Room temperature is cooled to after answering 4-6 hours, solvent is removed under reduced pressure, 20-40 milliliters of water are added, there is chemistry by extracting, being dried to obtain
The cautious lattice acid 2,6- dichloro benzyl esters of formula 7；
Step 2：Anhydrous Lithium chloride, tetrahydrofuran and diisopropylamine are inserted in reactor, -30 DEG C are cooled to -- after 45 DEG C, plus
Enter the tetrahydrofuran solution, equimolar highly basic and the cautious lattice acid with chemical formula 7 of the three epimino lactones with chemical formula 2
The tetrahydrofuran solution of 2,6- dichloro benzyl esters, reacts 25-35 hours in -5 DEG C -5 DEG C, is quenched, be concentrated under reduced pressure with saturated ammonium chloride
Tetrahydrofuran is reclaimed, wherein, anhydrous Lithium chloride, diisopropylamine and the three epimino lactones with chemical formula 2 and cautious lattice acid 2,6-
The molar ratio of dichloro benzyl ester is 2.0~8.0:1.0~1.2:1:1.0~1.3；
Step 3：Product in step 2 is added into a certain amount of water, is concentrated to give through extraction, washing, drying with chemical formula 10
Compound and compound with chemical formula 11 mixture；
Step 4：Mixture in step 3 is separated by recrystallizing, the compound with chemical formula 10 is respectively obtained and has
Chemical formula is 11 compound；
Step 5：It will be dissolved in chemical formula for 10 compound in 4-6N hydrochloric acid, and be heated to 70-90 DEG C, after stirring 3-5 hours
It is cooled to room temperature；
Step 6：By reaction product in step 5 through corresponding oxyphor is obtained by extraction, remove under reduced pressure and volume ratio is added after hydrochloric acid
For 1:1 absolute ethyl alcohol and expoxy propane mixed liquor, backflow obtains solid matter, and product (2S, 3S, 4R) -3 is obtained after filter,
4- dimethyl glutamic acid.
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