CN106478439A - A kind of preparation method of O tert-butyl group L threonine tert-butyl ester - Google Patents
A kind of preparation method of O tert-butyl group L threonine tert-butyl ester Download PDFInfo
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- 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
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Abstract
The invention discloses a kind of preparation method of O tert-butyl group L threonine tert-butyl ester, comprise the following steps：Add L threonine and hydrophilic organic solvent, Deca organic acid catalyst in 20 DEG C～20 DEG C in a kettle.；Described hydrophilic organic solvent is the ether solvent of C8 containing C3；Add isobutene. at 50 DEG C～0 DEG C after completion of the reaction, after then continuing reaction at this temperature 12 144 hours, terminate reaction；Add water and ammonia to pH=7.5 8.0 at 5 DEG C～5 DEG C, separate organic faciess, aqueous phase adds ethyl acetate to extract, merge organic faciess, washing organic faciess, organic faciess drying, concentrating under reduced pressure obtain O tert-butyl group L threonine tert-butyl ester crude product, and crude product acetic acid becomes salt to carry out purification.The preparation method of the present invention has the advantages that process is simple, safety and environmental protection, high yield low cost, is suitable for big production requirement.
Description
Technical field
The present invention relates to production peptide and protein, it is specifically related to a kind of system of the O- tert-butyl group-L-Threonine tert-butyl ester
Preparation Method.
Background technology
The O- tert-butyl group-L-Threonine tert-butyl ester is synthesis polypeptide and the important source material of protein, United States Patent (USP) US4601852
Disclose the O- tert-butyl group-application in synthetic insulin human for the L-Threonine tert-butyl ester, at present the O- of report synthesis both at home and abroad
The method of the tert-butyl group-L-Threonine tert-butyl ester only has two kinds, and first method is with L-Threonine and isobutene. as raw material, dense
Target compound is generated under the catalysis of sulphuric acid.One-step method and three-step approach are protected and be divided into according to L-Threonine to this method whether.
Journal of American Chemical Society85,201-207 (1963) describes first by the ammonia in L-Threonine
Base is protected with benzyloxycarbonyl group, is then reacted with isobutene. and concentrated sulphuric acid again, finally sloughs protection group with 10% palladium charcoal
Benzyloxycarbonyl group obtains the three-step approach of final product, and total recovery is 30%, as shown in formula one.WO2005023756 patent reported by
L-Threonine and isobutene. generate the target product O- tert-butyl group-L-Threonine tert-butyl ester through single step reaction under the catalysis of concentrated sulphuric acid
Method, but yield only has 43.22%, as shown in formula two.Second method is Tetrahedron Letters 53 (2012)
The method that 641-645 introduces, that is, with L-Threonine and methyl tertiary butyl ether(MTBE) as raw material, room temperature in the presence of concentrated sulphuric acid and molecular sieve
Reaction obtains target product, and yield only has 35%, as formula three.
By relatively above-mentioned three kinds of methods, can learn：Method described in formula one needs three-step reaction just can obtain target
Product, and need to be carried out catalytic hydrogenation with expensive palladium/charcoal, complex process, not only high cost, to there is certain safety hidden
Suffer from, and yield also only has 30%.Although method process is simple described in formula two, only need single step reaction just can obtain required chemical combination
Thing, yield is also highest one in the method that current open source literature is reported, but in reaction, per kilogram L-Threonine needs to add
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
For -6.9 DEG C, being that one kind is inflammable and explosive has phase gas, and this brings great potential safety hazard not only to big production, and causes greatly
Waste, there is no any benefit to reduces cost and environmental conservation.Described in formula three, method replaces isobutene. with methyl tertiary butyl ether(MTBE)
To synthesize the O- tert-butyl group-L-Threonine tert-butyl ester, potential safety hazard during big production is eliminated on great achievement degree very much, and process is simple,
But in actual applications, but cannot reappear the different data of document report and result.
In order to meet peptide and protein, the particularly synthesis of insulin, research and develop one and be suitable for big production, Quan An
Environmental protection, high yield synthesis technique inexpensive, simple to operate is very necessary and significant.
Content of the invention
The technical problem to be solved overcomes in the existing preparation O- tert-butyl group-L-Threonine tert-butyl ester technology
Deficiency, provides the preparation O- tert-butyl group-L- Soviet Union of a kind of process is simple, safety and environmental protection, high yield low cost, suitable big production requirement
The synthetic method of the propylhomoserin tert-butyl ester.
The technical scheme solving above-mentioned technical problem is as follows.
A kind of preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester, comprises the following steps：
(1) L-Threonine and hydrophilic organic solvent are added in a kettle., Deca organic acid is urged in -20 DEG C～20 DEG C
Agent；Described hydrophilic organic solvent is ether solvent containing C3-C8；Described organic acid catalyst is selected from methanesulfonic acid, fluoroform sulphur
Acid, trifluoroacetic acid, benzenesulfonic acid any one, its weight with L-Threonine is than for 3～20：1；Described ether solvent containing C3-C8
Selected from oxolane, Pentamethylene oxide., 2- methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, 1,3- bis-
Alkane, 1,3- dioxolane, three alkane, diethylene glycol dimethyl ether, diethyl carbitol, diethylene glycol ethyl methyl ether, triethylene glycol dimethyl ether.
In any one, its weight with L-Threonine is than for 3～15：1；
(2) add isobutene. at -50 DEG C～0 DEG C after catalyst finishes, then continue reaction 12-144 at this temperature little
When after terminate reaction；The weight of the isobutene. and the L-Threonine that add ratio is for 3～15：1；
(3) add water and 20-25% ammonia to pH=7.5-8.0 at -5 DEG C～5 DEG C, separate organic faciess, aqueous phase adds second
Acetoacetic ester extracts, and merges organic faciess, washes organic faciess, organic faciess drying, concentrating under reduced pressure obtain the O- tert-butyl group-tertiary fourth of L-Threonine
Ester crude product, crude product acetic acid becomes salt to carry out purification, obtains final product.
The yield of above-mentioned preparation method is more than 60%, and purity is more than 99%, and its synthetic route is as shown in formula four.
The present invention, through selecting organic acid catalyst, optimizes reaction condition, has obtained a kind of new O- tert-butyl group-L- Soviet Union
The preparation method of the propylhomoserin tert-butyl ester, this preparation method yield be more than 60%, purity be more than 99%, and process is simple, safety and environmental protection,
Low cost, suitable big production requirement.
Specific embodiment
In one embodiment of the present of invention, the preparation method of the described O- tert-butyl group-L-Threonine tert-butyl ester, walk including following
Suddenly：
(1) L-Threonine and hydrophilic organic solvent are added in a kettle., in -20～20 DEG C of Deca certain amount of organic acid
Catalyst；Described hydrophilic organic solvent is ether solvent containing C3-C8；
(2) add isobutene. at -50～0 DEG C after catalyst finishes, then continue reaction 12-144 hour at this temperature
After terminate react；
(3) water and 20-25% (mass fraction) ammonia is added to pH=7.5-8.0, to separate organic faciess at -5 DEG C～5 DEG C,
Aqueous phase adds ethyl acetate to extract, and merges organic faciess, washes organic faciess, organic faciess drying, concentrating under reduced pressure obtain the O- tert-butyl group-L-
Threonine tert-butyl ester crude product, crude product acetic acid becomes salt to carry out purification.
Hydrophilic organic solvent of the present invention refers to ether solvent containing C3-C8, including oxolane, Pentamethylene oxide., 2-
Methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, 1,3- dioxane, 1,3- dioxolane, three alkane,
Diethylene glycol dimethyl ether, diethyl carbitol, diethylene glycol ethyl methyl ether, triethylene glycol dimethyl ether. etc., preferably oxolane, Pentamethylene oxide.,
2- methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, 1,3- dioxane, most preferably glycol dinitrate
Ether, dioxane.Its weight with L-Threonine is than for 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, benzenesulfonic acid etc., preferably first
Sulfonic acid, trifluoromethanesulfonic acid, most preferably trifluoromethanesulfonic acid, its weight with L-Threonine is than for 3～20：1, preferably 4～10：1,
Preferably 4～6：1.
Isobutene. of the present invention adds in reactor with liquid form under normal circumstances, its weight ratio with L-Threonine
For 3～15：1, preferably 4～10：1, most preferably 5～7：1.
Preferably -10 DEG C～10 DEG C of temperature organic acid being added drop-wise in reaction system of the present invention, most preferably -5 DEG C～5
℃.
Preferably -20 DEG C～-5 DEG C of temperature isobutene. being added in reaction system of the present invention, most preferably -15 DEG C～-
10℃.
Preferably -20 DEG C～-5 DEG C of reaction temperature preparing the O- tert-butyl group-L-Threonine tert-butyl ester of the present invention, optimum
- 15 DEG C～-10 DEG C of choosing.
The response time preparing the O- tert-butyl group-L-Threonine tert-butyl ester of the present invention is 12～144 hours, preferably 36～
72 hours, most preferably 36～48 hours.
Below by specific embodiment, the preparation of the O- tert-butyl group-L-Threonine tert-butyl ester of the present invention is made further
Bright.
Embodiment one, the preparation of the O- tert-butyl group-L-Threonine tert-butyl ester
(1) double L-Threonine 250g and 1750 grams of glycol dimethyl ether are added in 5000ml there-necked flask be cooled to -10 to -
5 DEG C, then 1000 grams of trifluoromethanesulfonic acid of Deca at -5 to 5 DEG C；
(2) finish and add 1250 grams of isobutene. at -15 DEG C to -10 DEG C, controlling reaction temperature is anti-at -15 DEG C to -10 DEG C
Answer 48 hours；
(3) finish, add 2500 grams of water at -5 DEG C to 5 DEG C, add 1500 grams of 20-25% ammonia under equality of temperature to pH=
7.5-8.0, split-phase, aqueous phase continuously add ethyl ester 1000ml, 500ml extract secondary, merge organic faciess again use 250ml, 250ml,
250ml washes three times, 50 grams of dryings of anhydrous sodium sulfate, and 50 DEG C are evaporated to dry, obtain 360 grams of crude product, and purity 95% (GC) is received
Rate 70.44%.Crude product can carry out purification by the following method：360 grams of crude product adds n-hexane 1500g stirring molten clear,
Add activated carbon 5g, after decolouring 1 hour at 25-35 DEG C, filter, then with n-hexane 150g filter wash cake.Add at 15-25 DEG C
93.0 grams of glacial acetic acid (360 × 95% 231.33 × 1.05 × 60=88.0 gram of ÷), after stirring 2 hours under equality of temperature, slow cooling
To 0 to 5 DEG C of stirred crystallization 2 hours, centrifugation crystallization, with a small amount of ice n-hexane drip washing crystallization, wet crystallization is vacuum dried at 45 DEG C
Obtain 415 grams of product, purity 99.40%, yield 67.87% afterwards；415 grams of acetic acid product salts are added in 800 grams of water, stirring is molten clear
Add n-hexane 500ml afterwards, add about 120 grams of sodium bicarbonate to system pH=7.5-8.0, split-phase, aqueous phase with 500ml just continues
Hexane extraction is secondary, and aqueous phase discards, and merges organic faciess, washes after three organic faciess with each 300ml, anhydrous sodium sulfate drying, and 45
At DEG C, concentrating under reduced pressure obtains 326.20 grams of colourless liquid, purity 99.69%, yield 67.20%.
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).
Embodiment two, the preparation of the O- tert-butyl group-L-Threonine tert-butyl ester
(1) double L-Threonine 250g and 1750 grams of dioxane are added in 5000ml there-necked flask and are cooled to -10 DEG C to -5 DEG C,
Then 1250 grams of methanesulfonic acids of Deca at -5 DEG C to 5 DEG C；
(2) finish and add 1250 grams of isobutene. at -15 DEG C to -10 DEG C, controlling reaction temperature is anti-at -15 DEG C to -10 DEG C
Answer 48 hours；
(3) reaction finishes, adds 2500 grams of water at -5 DEG C to 5 DEG C, adds 1500 grams of 20-25% ammonia to PH under equality of temperature
=7.5-8.0, split-phase, aqueous phase continuously add ethyl ester 1000ml, 500ml extract secondary, merge organic faciess again use 250ml,
250ml, 250ml wash three times, 50 grams of dryings of anhydrous sodium sulfate, and 50 DEG C are evaporated to dry, obtain 340 grams of crude product, purity 95%
(GC), yield 66.6%.Crude product can carry out purification by the following method：340 grams of crude product adds n-hexane 1500g stirring
Molten clear, add activated carbon 5g, after decolouring 1 hour at 25-35 DEG C, filter, then with n-hexane 150g filter wash cake.At 15-25 DEG C
Lower 88.0 grams of glacial acetic acid of addition (340 × 95% 231.33 × 1.05 × 60=88.0 gram of ÷), after stirring 2 hours, delays under equality of temperature
Slowly it is cooled to 0 DEG C to 5 DEG C stirred crystallization 2 hours, centrifugation crystallization, with a small amount of ice n-hexane drip washing crystallization, wet crystallization is at 45 DEG C
392.2 grams of product, purity 99.53%, yield 64.10% is obtained after vacuum drying.392.2 grams of acetic acid product salts are added 800 grams
In water, stirring is molten to add n-hexane 500ml clearly afterwards, adds about 115 grams of sodium bicarbonate to system pH=7.5-8.0, split-phase, aqueous phase
Continue secondary with the extraction of 500ml n-hexane, aqueous phase discards, and merges organic faciess, wash after three organic faciess with each 300ml, anhydrous
Sodium sulfate is dried, and at 45 DEG C, concentrating under reduced pressure obtains 307.5 grams of colourless liquid, purity 99.71%, yield 63.40%.
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).
Embodiment three, the preparation of the O- tert-butyl group-L-Threonine tert-butyl ester
(1) double L-Threonine 250g and 1750 grams of glycol dimethyl ether are added in 5000ml there-necked flask and are cooled to -10 DEG C
To -5 DEG C, then 1250 grams of trifluoroacetic acids of Deca at -5 to 5 DEG C；
(2) finish and add 1250 grams of isobutene. at -15 DEG C to -10 DEG C, controlling reaction temperature is anti-at -15 DEG C to -10 DEG C
Answer 48 hours；
(3) finish, add 2500 grams of water at -5 DEG C to 5 DEG C, add 1500 grams of 20% ammonia under equality of temperature to pH=7.5-
8.0, split-phase, aqueous phase continuously add ethyl ester 1000ml, 500ml extract secondary, merge organic faciess again use 250ml, 250ml, 250ml
Wash three times, 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are evaporated to dry, obtain 335 grams of crude product, purity 91% (GC), yield
62.28%.Carry out obtaining after purification 293.72 grams of sterling, purity 99.61%, yield 60.50% 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's (embodiment carrying out by WO2005023256)
Double L-Threonine 250g and 4350 grams of glycol dimethyl ether (5000ml) are added to cooling in 10000ml there-necked flask
To -10 DEG C to -5 DEG C, then 1250 gram of 98% concentrated sulphuric acid of Deca at -10 DEG C to -5 DEG C, finish addition isobutene. below 5 DEG C
4700 grams, controlling reaction temperature is reacted 24 hours at 0 DEG C to 5 DEG C.Finish, add 2500 grams of water at -5 DEG C to 5 DEG C, under equality of temperature
Add 1500 grams of 20% ammonia to pH=7.5-8.0, split-phase, aqueous phase continuously add ethyl ester 1000ml, 500ml extract secondary,
Merge organic faciess to be washed three times with 250ml, 250ml, 250ml again, 50 grams of dryings of anhydrous sodium sulfate, 50 DEG C are evaporated to dry, obtain
210 grams of crude product, purity 90% (GC), yield 38.92%.Crude product is carried out obtaining after purification sterling by above-described embodiment method
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).
Embodiment described above only have expressed the several embodiments of the present invention, and its description is more concrete and detailed, but simultaneously
Therefore the restriction to the scope of the claims of the present invention can not 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, some deformation can also be made and improve, these broadly fall into the guarantor of the present invention
Shield scope.Therefore, the protection domain of patent of the present invention should be defined by claims.
Claims (10)
- The preparation method of the 1.O- tert-butyl group-L-Threonine tert-butyl ester is it is characterised in that comprise the following steps：(1) L-Threonine and hydrophilic organic solvent, Deca organic acid catalysis in -20 DEG C～20 DEG C are added in a kettle. Agent；Described hydrophilic organic solvent is ether solvent containing C3-C8；Described organic acid catalyst be selected from methanesulfonic acid, trifluoromethanesulfonic acid, Trifluoroacetic acid, benzenesulfonic acid any one, its weight with L-Threonine is than for 3～20：1；Described ether solvent containing C3-C8 is selected from Oxolane, Pentamethylene oxide., 2- methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, 1,3- dioxane, 1st, 3- dioxolane, three alkane, diethylene glycol dimethyl ether, diethyl carbitol, diethylene glycol ethyl methyl ether, appointing in triethylene glycol dimethyl ether. One kind, its weight with L-Threonine is than for 3～15：1；(2) add isobutene. at -50 DEG C～0 DEG C after catalyst adds, after then continuing reaction 12-144 hour at this temperature Terminate reaction；The weight of the isobutene. and the L-Threonine that add ratio is for 3～15：1；(3) water and 20- are added at -5 DEG C～5 DEG C 25% ammonia, to pH=7.5-8.0, separates organic faciess, and aqueous phase adds ethyl acetate to extract, and merges organic faciess, washes organic faciess, Organic faciess drying, concentrating under reduced pressure obtain the O- tert-butyl group-L-Threonine tert-butyl ester, and crude product acetic acid becomes salt to carry out purification.
- 2. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 1 is it is characterised in that described contain C3-C8 ether solvent be oxolane, Pentamethylene oxide., 2- methyltetrahydrofuran, glycol dimethyl ether, ethylene glycol diethyl ether, two Alkane or 1,3- dioxane；Its weight ratio 4～10 with L-Threonine：1.
- 3. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 2 is it is characterised in that described contain C3-C8 ether solvent is glycol dimethyl ether, dioxane, and its weight with L-Threonine ratio is for 5～7：1.
- 4. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 1 is it is characterised in that described have Machine acid catalyst is methanesulfonic acid, trifluoromethanesulfonic acid, and its weight with L-Threonine ratio is for 4～10：1.
- 5. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 4 is it is characterised in that described have Machine acid catalyst is trifluoromethanesulfonic acid, and its weight with L-Threonine ratio is for 4～6：1.
- 6. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 1 is it is characterised in that step (2) Described in isobutene. be to add in reactor with liquid form, the isobutene. of addition and the weight of L-Threonine ratio is for 4～10：1.
- 7. the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 6 preparation method it is characterised in that add The weight of isobutene. and L-Threonine is than for 5～7：1.
- 8. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to any one of claim 1-7, its feature exists In, in step (1), Deca organic acid catalyst in -10 DEG C～10 DEG C, most preferably -5 DEG C～5 DEG C.
- 9. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to any one of claim 1-7, its feature exists In in step (2), reaction temperature is -20 DEG C～-5 DEG C, and the response time is 36～72 hours.
- 10. the preparation method of the O- tert-butyl group-L-Threonine tert-butyl ester according to claim 9 is it is characterised in that step (2) in, reaction temperature is -15 DEG C～-10 DEG C, and the response time is 36～48 hours.
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