CN106478439B - A kind of preparation method of O- tertiary butyls-L-threonine tert-butyl ester - Google Patents
A kind of preparation method of O- tertiary butyls-L-threonine tert-butyl ester Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Abstract
The invention discloses a kind of preparation methods of O tertiary butyls L threonine tert-butyl esters, include the following steps：L threonines and hydrophilic organic solvent are added in a kettle, organic acid catalyst is added dropwise in 20 DEG C~20 DEG C；The hydrophilic organic solvent is the ether solvents of C8 containing C3；Isobutene is added at 50 DEG C~0 DEG C after completion of the reaction, reaction was completed after then the reaction was continued at this temperature 12 144 hours；Water and ammonium hydroxide are added at 5 DEG C~5 DEG C to pH=7.5 8.0, separates organic phase, ethyl acetate extraction is added in water phase, merge organic phase, wash organic phase, organic phase through drying, be concentrated under reduced pressure O tertiary butyl L threonine tert-butyl ester crude products, crude product are purified with acetic acid at salt.The preparation method of the present invention has the advantages that simple for process, safety and environmental protection, in high yield low cost, suitable big production requirement.
Description
Technical field
The present invention relates to production peptide and proteins, are specifically related to a kind of system of O- tertiary butyls-L-threonine tert-butyl ester
Preparation Method.
Background technology
O- tertiary butyls-L-threonine tert-butyl ester is synthesis polypeptide and the important source material of protein, United States Patent (USP) US4601852
O- tertiary butyls-application of the L-threonine tert-butyl ester in artificial synthesized actrapid monotard is disclosed, at present the O- of report synthesis both at home and abroad
There are two types of the methods of tertiary butyl-L-threonine tert-butyl ester, and first method is using L-threonine and isobutene as raw material, dense
Target compound is generated under the catalysis of sulfuric acid.This method is divided into one-step method and three-step approach according to whether L-threonine is protected.
Journal of American Chemical Society85,201-207 (1963) are described the ammonia in L-threonine first
Base is protected with benzyloxycarbonyl group, is then reacted again with isobutene and the concentrated sulfuric acid, finally sloughs protecting group with 10% palladium charcoal
Benzyloxycarbonyl group obtains the three-step approach of final product, total recovery 30%, as shown in formula one.WO2005023756 patents reported by
L-threonine and isobutene generate target product O- tertiary butyls-L-threonine tert-butyl ester under the catalysis of the concentrated sulfuric acid through single step reaction
Method, but yield only has 43.22%, as shown in formula two.Second method is Tetrahedron Letters 53 (2012)
The method that 641-645 is introduced, i.e., using L-threonine and methyl tertiary butyl ether(MTBE) as raw material, the room temperature in the presence of concentrated sulfuric acid and molecular sieve
Target product is obtained by the reaction, yield only has 35%, such as formula three.
By comparing above-mentioned three kinds of methods, can learn：Method described in formula one needs three-step reaction that can just obtain target
Product, and need to carry out catalytic hydrogenation with expensive palladium/charcoal, complex process, it is not only of high cost, there are certain safety is hidden
Suffer from, and yield also only has 30%.Method is although simple for process described in formula two, only needs single step reaction that can obtain required chemical combination
Object, yield be also current open source literature report method in highest one, but per kilogram L-threonine needs to be added in reacting
The glycol dimethyl ether of 17.34 times of weight ratios makees the isobutene of solvent and 18.8 times of weight as raw material, due to isobutene boiling point
It it is -6.9 DEG C, being that one kind is inflammable and explosive has phase gas, this not only gives big production to bring great security risk, but also causes greatly
Waste, does not have any benefit to reducing cost and environmental protection.Method replaces isobutene with methyl tertiary butyl ether(MTBE) described in formula three
It synthesizes O- tertiary butyls-L-threonine tert-butyl ester, security risk when big production is eliminated very much on great achievement degree, and simple for process,
But it in practical applications, but can not reappear document report different data and result.
In order to meet the synthesis of peptide and protein, especially insulin, researchs and develops one and be suitble to big production, Quan An
Environmentally friendly, high yield low cost, synthesis technology easy to operate are very necessary and significant.
Invention content
The technical problem to be solved by the present invention is to overcome existing prepare in O- tertiary butyls-L-threonine tert-butyl ester technology
Deficiency, provide a kind of simple for process, safety and environmental protection, in high yield low cost, be suitble to the preparation O- tertiary butyls-L- Soviet Unions of big production requirement
The synthetic method of the propylhomoserin tert-butyl ester.
The technical solution for solving above-mentioned technical problem is as follows.
A kind of preparation method of O- tertiary butyls-L-threonine tert-butyl ester, includes the following steps：
(1) L-threonine and hydrophilic organic solvent are added in a kettle, organic acid is added dropwise in -20 DEG C~20 DEG C and urges
Agent；The hydrophilic organic solvent is ether solvent containing C3-C8；The organic acid catalyst is selected from methanesulfonic acid, trifluoro methylsulphur
Acid, trifluoroacetic acid, benzene sulfonic acid it is any, be 3~20 with the weight ratio of L-threonine：1；The ether solvent containing C3-C8
Selected from tetrahydrofuran, oxinane, 2- methyltetrahydrofurans, glycol dimethyl ether, ethylene glycol diethyl ether, dioxanes, 1,3- bis-
Oxane, 1,3- dioxolane, trioxanes, diethylene glycol dimethyl ether, diethyl carbitol, diethylene glycol (DEG) ethyl methyl ether, triglyme
Any one of, the weight ratio with L-threonine is 3~15：1；
(2) isobutene is added after catalyst at -50 DEG C~0 DEG C, then the reaction was continued at this temperature, and 12-144 is small
When after reaction was completed；The isobutene of addition and the weight ratio of L-threonine are 3~15：1；
(3) water and 20-25% ammonium hydroxide are added at -5 DEG C~5 DEG C to pH=7.5-8.0, separates organic phase, second is added in water phase
Acetoacetic ester extract, merge organic phase, wash organic phase, organic phase through drying, O- tertiary butyls-tertiary fourth of L-threonine is concentrated under reduced pressure to obtain
Ester crude product, crude product with acetic acid at salt purify to get.
The yield of above-mentioned preparation method is more than 60%, and purity is more than 99%, and synthetic route is as shown in formula four.
The present invention optimizes reaction condition, has obtained a kind of new O- tertiary butyls-L- Soviet Unions by selecting organic acid catalyst
The preparation method of the propylhomoserin tert-butyl ester, the preparation method yield be more than 60%, purity be more than 99%, and simple for process, safety and environmental protection,
Low cost is suitble to big production requirement.
Specific implementation mode
In one embodiment of the present of invention, the preparation method of the O- tertiary butyls-L-threonine tert-butyl ester, including following step
Suddenly：
(1) L-threonine and hydrophilic organic solvent are added in a kettle, certain amount of organic acid is added dropwise at -20~20 DEG C
Catalyst；The hydrophilic organic solvent is ether solvent containing C3-C8；
(2) isobutene is added after catalyst at -50~0 DEG C, then the reaction was continued at this temperature 12-144 hours
Reaction was completed afterwards；
(3) water and 20-25% (mass fraction) ammonium hydroxide are added at -5 DEG C~5 DEG C to pH=7.5-8.0, separates organic phase,
Water phase be added ethyl acetate extraction, merge organic phase, wash organic phase, organic phase through drying, O- tertiary butyls-L- is concentrated under reduced pressure to obtain
Threonine tert-butyl ester crude product, crude product are purified with acetic acid at salt.
Hydrophilic organic solvent of the present invention refers to ether solvent containing C3-C8, including tetrahydrofuran, oxinane, 2-
Methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, dioxanes, 1,3- dioxanes, 1,3- dioxolane, trioxanes,
Diethylene glycol dimethyl ether, diethyl carbitol, diethylene glycol (DEG) ethyl methyl ether, triglyme etc., preferably tetrahydrofuran, oxinane,
2- methyltetrahydrofurans, glycol dimethyl ether, ethylene glycol diethyl ether, dioxanes, 1,3- dioxanes, most preferably glycol dinitrate
Ether, dioxanes.The weight ratio of itself and L-threonine is 3~15：1, preferably 4~10：1, most preferably 5~7：1.
Organic acid catalyst of the present invention includes methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, benzene sulfonic acid etc., preferably first
Sulfonic acid, trifluoromethanesulfonic acid, most preferably trifluoromethanesulfonic acid, the weight ratio with L-threonine are 3~20：1, preferably 4~10：1, most
It is preferred that 4~6：1.
Isobutene of the present invention is added with liquid form in reaction kettle under normal conditions, the weight ratio with L-threonine
It is 3~15：1, preferably 4~10：1, most preferably 5~7：1.
It is of the present invention by organic acid be added drop-wise to the temperature in reaction system preferably -10 DEG C~10 DEG C, most preferably -5 DEG C~5
℃。
It is of the present invention by isobutene be added to the temperature in reaction system preferably -20 DEG C~-5 DEG C, most preferably -15 DEG C~-
10℃。
Preferably -20 DEG C~-5 DEG C of the reaction temperature of the present invention for preparing O- tertiary butyls-L-threonine tert-butyl ester, it is optimal
- 15 DEG C~-10 DEG C of choosing.
The reaction time of the present invention for preparing O- tertiary butyls-L-threonine tert-butyl ester be 12~144 hours, preferably 36~
72 hours, most preferably 36~48 hours.
The preparation of O- tertiary butyls-L-threonine tert-butyl ester of the present invention is made further below by specific embodiment
It is bright.
The preparation of embodiment one, O- tertiary butyls-L-threonine tert-butyl ester
(1) 1750 grams of double L-threonine 250g and glycol dimethyl ether are added in 5000ml there-necked flasks be cooled to -10 to -
5 DEG C, 1000 grams of trifluoromethanesulfonic acids are then added dropwise at -5 to 5 DEG C；
(2) it finishes and is arrived at -15 DEG C anti-at -10 DEG C to -10 DEG C of 1250 grams of isobutenes of addition, controlling reaction temperature at -15 DEG C
It answers 48 hours；
(3) it finishes, 2500 grams of water is added at -5 DEG C to 5 DEG C, 1500 grams of 20-25% ammonium hydroxide is added under equality of temperature to pH=
7.5-8.0, split-phase, it is secondary that water phase continuously adds ethyl ester 1000ml, 500ml extraction, merge organic phase use again 250ml, 250ml,
250ml is washed three times, and 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are concentrated to dryness, and obtains 360 grams of crude product, and purity 95% (GC) is received
Rate 70.44%.Crude product can be purified by the following method：360 grams of crude product is added normal hexane 1500g and stirs dissolved clarification,
Activated carbon 5g is added, after decolourize 1 hour at 25-35 DEG C, filters, then with normal hexane 150g filter wash cakes.It is added at 15-25 DEG C
93.0 grams of glacial acetic acid (360 × 95% ÷ 231.33 × 1.05 × 60=88.0 gram), after stirring 2 hours under equality of temperature, slow cooling
To 0 to 5 DEG C of stirred crystallization 2 hours, centrifugation crystallization was eluted with a small amount of ice normal hexane and is crystallized, and wet crystallization is dried in vacuo at 45 DEG C
415 grams of product, purity 99.40%, yield 67.87% are obtained afterwards；415 grams of acetic acid product salts are added in 800 grams of water, dissolved clarification is stirred
Normal hexane 500ml is added afterwards, about 120 grams of sodium bicarbonate is added to system pH=7.5-8.0, split-phase, water phase continues with 500ml just
Hexane extraction is secondary, and water phase discards, and merges organic phase, after each 300ml washings three times organic phase, anhydrous sodium sulfate drying, and 45
326.20 grams of colourless liquid, purity 99.69%, yield 67.20% are concentrated under reduced pressure to obtain at DEG C.
1HNMR (400MHz, CDCl3) δ=3.86 (m, 1H), δ=3.11 (d, 1H), δ=1.70 (Br, 2H), δ=1.45
(s, 9H), δ=1.21 (d, 3H), δ=1.16 (s, 9H).
The preparation of embodiment two, O- tertiary butyls-L-threonine tert-butyl ester
(1) by double L-threonine 250g He 1750 grams of dioxane is added in 5000ml there-necked flasks and is cooled to -10 DEG C to -5 DEG C,
Then 1250 grams of methanesulfonic acids are added dropwise at -5 DEG C to 5 DEG C；
(2) it finishes and is arrived at -15 DEG C anti-at -10 DEG C to -10 DEG C of 1250 grams of isobutenes of addition, controlling reaction temperature at -15 DEG C
It answers 48 hours；
(3) reaction finishes, 2500 grams of water is added at -5 DEG C to 5 DEG C, and 1500 grams of 20-25% ammonium hydroxide is added under equality of temperature to PH
=7.5-8.0, split-phase, it is secondary that water phase continuously adds ethyl ester 1000ml, 500ml extraction, merge organic phase use again 250ml,
250ml, 250ml are washed three times, and 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are concentrated to dryness, and obtain 340 grams of crude product, purity 95%
(GC), yield 66.6%.Crude product can be purified by the following method：Normal hexane 1500g stirrings are added in 340 grams of crude product
Activated carbon 5g is added in dissolved clarification, after decolourize 1 hour at 25-35 DEG C, filters, then with normal hexane 150g filter wash cakes.At 15-25 DEG C
Lower 88.0 grams of addition glacial acetic acid (340 × 95% ÷ 231.33 × 1.05 × 60=88.0 gram) after stirring 2 hours under equality of temperature, is delayed
Slow to be cooled to 0 DEG C to 5 DEG C stirred crystallization 2 hours, centrifugation crystallization is eluted with a small amount of ice normal hexane and is crystallized, and wet crystallization is at 45 DEG C
392.2 grams of product, purity 99.53%, yield 64.10% are obtained after vacuum drying.392.2 grams of acetic acid product salts are added 800 grams
In water, normal hexane 500ml is added after stirring dissolved clarification, about 115 grams of sodium bicarbonate is added to system pH=7.5-8.0, split-phase, water phase
Continue to use the extraction of 500ml normal hexanes secondary, water phase discards, and merges organic phase, anhydrous after each 300ml washings three times organic phase
Sodium sulphate is dried, and 307.5 grams of colourless liquid, purity 99.71%, yield 63.40% is concentrated under reduced pressure to obtain at 45 DEG C.
1HNMR (400MHz, CDCl3) δ=3.86 (m, 1H), δ=3.11 (d, 1H), δ=1.70 (Br, 2H), δ=1.45
(s, 9H), δ=1.21 (d, 3H), δ=1.16 (s, 9H).
The preparation of embodiment three, O- tertiary butyls-L-threonine tert-butyl ester
(1) 1750 grams of double L-threonine 250g and glycol dimethyl ether are added in 5000ml there-necked flasks and are cooled to -10 DEG C
To -5 DEG C, 1250 grams of trifluoroacetic acids are then added dropwise at -5 to 5 DEG C；
(2) it finishes and is arrived at -15 DEG C anti-at -10 DEG C to -10 DEG C of 1250 grams of isobutenes of addition, controlling reaction temperature at -15 DEG C
It answers 48 hours；
(3) it finishes, 2500 grams of water is added at -5 DEG C to 5 DEG C, 1500 grams of 20% ammonium hydroxide is added under equality of temperature to pH=7.5-
8.0, split-phase, it is secondary that water phase continuously adds ethyl ester 1000ml, 500ml extraction, merges organic phase and uses 250ml, 250ml, 250ml again
It washes three times, 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are concentrated to dryness, and obtain 335 grams of crude product, purity 91% (GC), yield
62.28%.It carries out obtaining 293.72 grams of sterling, purity 99.61%, yield 60.50% after purification by above-described embodiment method.
1HNMR (400MHz, CDCl3) δ=3.86 (m, 1H), δ=3.11 (d, 1H), δ=1.70 (Br, 2H), δ=1.45
(s, 9H), δ=1.21 (d, 3H), δ=1.16 (s, 9H).
Comparative example (embodiment carried out by WO2005023256)
Double L-threonine 250g and glycol dimethyl ether 4350 grams (5000ml) are added in 10000ml there-necked flasks and are cooled down
To -10 DEG C to -5 DEG C, 1250 gram of 98% concentrated sulfuric acid is then added dropwise at -10 DEG C to -5 DEG C, finishes the addition isobutene at 5 DEG C or less
4700 grams, controlling reaction temperature is reacted 24 hours at 0 DEG C to 5 DEG C.It finishes, 2500 grams of water is added at -5 DEG C to 5 DEG C, under equality of temperature
1500 grams of 20% ammonium hydroxide being added to pH=7.5-8.0, split-phase, it is secondary that water phase continuously adds ethyl ester 1000ml, 500ml extraction,
Merge organic phase to be washed three times with 250ml, 250ml, 250ml again, 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are concentrated to dryness, and obtain
210 grams of crude product, purity 90% (GC), yield 38.92%.Crude product is obtained into sterling after purification by above-described embodiment method progress
184 grams, purity 99.43%, yield 37.89%.
1HNMR (400MHz, CDCl3) δ=3.86 (m, 1H), δ=3.11 (d, 1H), δ=1.70 (Br, 2H), δ=1.45
(s, 9H), δ=1.21 (d, 3H), δ=1.16 (s, 9H).
Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously
Cannot the limitation to the scope of the claims of the present invention therefore be interpreted as.It should be pointed out that for those of ordinary skill in the art
For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the guarantor of the present invention
Protect range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (5)
1.O- the preparation method of tertiary butyl-L-threonine tert-butyl ester, which is characterized in that include the following steps：
(1) L-threonine and hydrophilic organic solvent are added in a kettle, organic acid catalysis is added dropwise in -20 DEG C~20 DEG C
Agent；The hydrophilic organic solvent is ether solvent containing C3-C8；The organic acid catalyst be selected from methanesulfonic acid, trifluoromethanesulfonic acid,
Trifluoroacetic acid, benzene sulfonic acid it is any, be 3~20 with the weight ratio of L-threonine：1；The ether solvent containing C3-C8 is second
Glycol dimethyl ether, dioxanes, the weight ratio with L-threonine are 5~7：1；
(2) isobutene is added after catalyst adds at -50 DEG C~0 DEG C, then the reaction was continued at a temperature of -15 DEG C~-10 DEG C
Reaction was completed after 36~48 hours；The isobutene is added in reaction kettle with liquid form, isobutene and the L- Soviet Unions ammonia of addition
The weight ratio of acid is 4~10：1；
(3) water and 20-25% ammonium hydroxide are added at -5 DEG C~5 DEG C to pH=7.5-8.0, separates organic phase, acetic acid second is added in water phase
Ester extract, merge organic phase, wash organic phase, organic phase through drying, be concentrated under reduced pressure O- tertiary butyls-L-threonine tert-butyl ester is thick
Product, crude product are purified with acetic acid at salt.
2. the preparation method of O- tertiary butyls-L-threonine tert-butyl ester according to claim 1, which is characterized in that described to have
Machine acid catalyst is methanesulfonic acid, trifluoromethanesulfonic acid, and the weight ratio with L-threonine is 4~10：1.
3. the preparation method of O- tertiary butyls-L-threonine tert-butyl ester according to claim 2, which is characterized in that described to have
Machine acid catalyst is trifluoromethanesulfonic acid, and the weight ratio with L-threonine is 4~6：1.
4. the preparation method of O- tertiary butyls-L-threonine tert-butyl ester according to claim 1, which is characterized in that addition
The weight ratio of isobutene and L-threonine is 5~7：1.
5. according to the preparation method of claim 1-4 any one of them O- tertiary butyls-L-threonine tert-butyl ester, feature exists
In in step (1), organic acid catalyst is added dropwise in -10 DEG C~10 DEG C.
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| CA2538175A1 (en) * | 2003-09-08 | 2005-03-17 | Wockhardt Limited | Method for the manufacture of l-threonine-o-(1,1-dimethylethyl)-1,1-dimethylethyl ester |
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