CN111233685B - Preparation method of racemic D/L-tert-leucine - Google Patents
Preparation method of racemic D/L-tert-leucine Download PDFInfo
- Publication number
- CN111233685B CN111233685B CN202010083292.5A CN202010083292A CN111233685B CN 111233685 B CN111233685 B CN 111233685B CN 202010083292 A CN202010083292 A CN 202010083292A CN 111233685 B CN111233685 B CN 111233685B
- Authority
- CN
- China
- Prior art keywords
- tert
- leucine
- acid
- racemic
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000002262 Schiff base Substances 0.000 claims abstract description 14
- 150000004753 Schiff bases Chemical class 0.000 claims abstract description 14
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- IAWVHZJZHDSEOC-UHFFFAOYSA-N 3,3-dimethyl-2-oxobutanoic acid Chemical compound CC(C)(C)C(=O)C(O)=O IAWVHZJZHDSEOC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- -1 ketone sulfate Chemical class 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- QDGMKZBNMLHUFX-UHFFFAOYSA-N 4,4-dimethyl-2-oxopentanoic acid Chemical compound CC(C)(C)CC(=O)C(O)=O QDGMKZBNMLHUFX-UHFFFAOYSA-N 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 abstract description 3
- 238000007039 two-step reaction Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- VBXFJLRUNKVZCE-UHFFFAOYSA-N 3,3-dimethyl-2-trityliminobutanoic acid Chemical compound CC(C)(C)C(=NC(C1=CC=CC=C1)(C2=CC=CC=C2)C3=CC=CC=C3)C(=O)O VBXFJLRUNKVZCE-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- FYGSHLFUTKXHCN-UHFFFAOYSA-N 3,3-dimethyl-2-[(2-methylpropan-2-yl)oxycarbonylimino]butanoic acid Chemical compound CC(C)(C)C(=NC(=O)OC(C)(C)C)C(=O)O FYGSHLFUTKXHCN-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 3
- BZVJOYBTLHNRDW-UHFFFAOYSA-N triphenylmethanamine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(N)C1=CC=CC=C1 BZVJOYBTLHNRDW-UHFFFAOYSA-N 0.000 description 3
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- YVZKICWRYOHMRD-UHFFFAOYSA-N tert-butyl 2-oxopropanoate Chemical compound CC(=O)C(=O)OC(C)(C)C YVZKICWRYOHMRD-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07C227/20—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 by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of racemic D/L-tert-leucine, belonging to the technical field of organic synthesis. Taking tert-butyl pyruvic acid as a raw material, and obtaining racemic D/L-tert-leucine through two-step reaction. First step with NH 2 And (4) carrying out a condensation reaction on the P to generate Schiff base. And in the second step, schiff base is reduced, acid is used for deprotection, and base is adjusted to an isoelectric point to obtain racemic D/L-tertiary leucine. The method has simple operation and high reaction yield, and the obtained racemate has purity of more than 99%.
Description
Technical Field
The invention relates to a preparation method of racemic D/L-tert-leucine, belonging to the technical field of organic synthesis.
Background
Racemic D/L-tert-leucine, england name 2-amino-3, 3-dimethylbutanic acid, CAS:33105-81-6. The racemic D/L-tert-leucine is non-natural amino acid and has special steric hindrance and hydrophobicity, so that the racemic D/L-tert-leucine can be widely applied in chemistry and biology, and the derivative of the tert-leucine can be used as an asymmetric template for inducing asymmetry in asymmetric synthesis to modify a polypeptide drug, so that the polypeptide drug achieves the effect of improving the drug effect. Therefore, the application of the compound in medicines and organisms is rapidly developing, and the compound is used for anti-cancer, anti-AIDS medicines, biological inhibitors H, peptides and the like.
At present, the compound has more and more application values, however, the synthetic literature of the compound is not reported much, wherein the literature [ US 2012/24589,2012,a1 ] and [ EP2502896,2012, A1] report that the D or L-configuration tertiary leucine is mainly adopted as a raw material and is racemized with alkali-ammonia water at high temperature to obtain racemic D/L-tertiary leucine with the yield of 92%.
Literature [ Tetrahedron Letters,1986, vol.27, #48, p.5865-5868] reports that racemic D/L-tert-leucine is obtained by using pinacolone as a raw material, synthesizing hydrazone with phenylhydrazine after oxidation, and performing high-pressure hydrogenation on the hydrazone under the condition of palladium carbon. The method uses palladium carbon, has high cost and needs high-pressure equipment.
Therefore, it is necessary to develop a method for synthesizing racemic D/L-tert-leucine, and to find a preparation process which is simple and convenient to synthesize, easy to purify, safe to operate, and suitable for industrial amplification.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a method for preparing racemic D/L-tert-leucine by taking tert-butyl pyruvic acid as a raw material and carrying out two-step reaction. First step with NH 2 And (4) carrying out a condensation reaction on the P to generate Schiff base. And the second step is to reduce Schiff base, then to remove protection by acid, and to adjust base to isoelectric point, to obtain racemic D/L-tert-leucine. The method has simple operation and high reaction yield, and the obtained racemate has purity of more than 99%.
The preparation method of the racemic D/L-tert-leucine provided by the invention comprises the following steps:
the first step is as follows: condensation reaction
Reacting tert-butyl pyruvic acid and NH 2 -P is dissolved in an organic solvent and heated for water-separating condensation to generate Schiff base;
the second step is that: reduction and deprotection
Dissolving the Schiff base obtained in the first step in an organic solvent, adding a reducing agent for reaction, carrying out acidolysis deprotection, adding a base for adjusting to an isoelectric point, and obtaining racemic D/L-tert-leucine.
The reaction equation is used to represent the following:
further, in the above technical solution, the NH in the first step 2 -P is selected from tert-butyl carbamate or triphenylmethylamine. P is Boc or Tr (trityl).
Further, in the above technical solution, the organic solvent in the first step is selected from toluene, dioxane, xylene or a mixture thereof in any proportion.
Further, in the above technical scheme, the condensation reaction can be accelerated by adding a catalyst in the first step, and the catalyst is selected from anhydrous ketone sulfate or p-toluenesulfonic acid.
Further, in the above technical solution, in the first step, the mass ratio of the tert-butyl pyruvic acid to the lewis acid is 1.1-0.05; tert-butyl pyruvate with NH 2 -a molar ratio of P from 1.05 to 1.12.
Further, in the above technical solution, the reducing agent in the second step is selected from sodium borohydride or lithium borohydride.
Furthermore, in the technical scheme, the reducing agent is added into the second step in a molar amount of 1.0-2.0 of the tert-butyl pyruvic acid.
Further, in the above technical solution, the organic solvent in the second step is selected from 2-methyltetrahydrofuran or tetrahydrofuran.
Further, in the above technical scheme, the second deprotection acid is selected from hydrochloric acid or hydrobromic acid;
further, in the above technical scheme, the second step alkali is selected from potassium hydroxide, potassium carbonate, sodium hydroxide or sodium carbonate; isoelectric point pH =5.9-6.2.
Advantageous effects of the invention
The invention takes tert-butyl pyruvic acid as a raw material and is finished by two-step reaction. The first step is condensation reaction with protected amino group to produce Schiff base. Secondly, schiff base is reduced, then the protecting group of amino is removed under acidic condition, and finally, alkali is used for adjusting pH to isoelectric point to obtain racemic D/L-tert-leucine. The method is simple and convenient to operate, the reaction yield is high, the obtained purity and content are more than 99%, the single impurity is less than 0.2%, the racemic D/L-tert-leucine is 0-1.5% ee, and the method has potential process amplification prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples.
These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
The experimental methods of the present invention, in which specific conditions are not specified in the following examples, are generally carried out under conventional conditions.
The starting materials or reagents used in the following examples of the present invention are commercially available unless otherwise specified.
The average room temperature described in the following examples of the invention is 20-25 ℃. Unless otherwise indicated, the reagents are not specifically indicated and are all used without purification. All solvents were purchased from commercial suppliers and used without treatment. The reaction was analyzed by TLC, HPLC, and the termination of the reaction was judged by the consumption of starting material.
The first step is as follows: synthesis of 2-P-imino-3, 3-dimethylbutyric acid
Example 1
Under the protection of nitrogen, 130.2g (1.0 mol) of t-butylpyruvic acid, 6.5g of p-toluenesulfonic acid and 500mL of toluene were charged into a reaction flask. The temperature was raised to 50 to 55 ℃ with stirring, and a toluene solution containing 140g (1.2 mol,1.2 eq) of tert-butyl carbamate was slowly added dropwise. After the addition, the internal temperature was 40-55 ℃ and the water was allowed to separate under reflux for 3 hours under vacuum, and the starting material disappeared by TLC detection (< 0.4% by HPLC). After the reaction is finished, the mixture is concentrated to remove toluene and is replaced by ethanol, n-heptane is added for pulping, and 204g of Schiff base 2-tert-butoxycarbonylimino-3, 3-dimethylbutyric acid is obtained by filtration, the yield is 89%, and the HPLC purity is 98.8%. 1 HNMR(400MHz,CDCl 3 ):11.3(s,1H),1.4(s,9H),1.1(s,9H).
Example 2
130.2g (1 mol) of t-butylpyruvic acid, 6.5g of p-toluenesulfonic acid and 450mL of dioxane were charged into a reaction flask. Heating to 50-55 ℃ while stirring, slowly dropwise adding dioxane solution containing 140g (1.2 mol,1.2 eq) of tert-butyl carbamate, heating to reflux after dropwise adding is finished, distilling out about 110mL of solvent, and detecting by HPLC that the raw material is less than 0.4%. After the reaction is finished, the product is concentrated to remove dioxane and is replaced by ethanol, n-heptane is added for pulping, and 202.7g of Schiff base 2-tert-butyloxycarbonylimino-3, 3-dimethylbutyric acid is obtained by filtration, the yield is 88.4 percent, and the HPLC purity is 99.3 percent.
Example 3
130.2g (1 mol) of trimethylpyruvic acid, 13g of anhydrous ketone sulfate and 500mL of xylene are put into a reaction bottle under the protection of nitrogen. Heating to 50-55 ℃ under stirring, slowly dropwise adding a dimethylbenzene solution containing 273g (1.05 eq) of triphenylmethylamine, and after dropwise adding, carrying out vacuum reflux and water separation at an internal temperature of 60-55 ℃ for 3 hours, wherein the HPLC detection shows that the raw material is less than 0.5%. Filtering after the reaction is finished, concentrating the filtrate to remove dimethylbenzene and N-methyl tetrahydropyrrole, replacing the dimethylbenzene and N-methyl tetrahydropyrrole with methanol, cooling to 15-20 ℃, pulping for 1 hour, and filtering to obtain 339.2g of Schiff base 2-triphenylmethylimino-3, 3-dimethylbutyric acid, wherein the yield is 91.3 percent, and the HPLC purity is 99.1 percent. 1 HNMR(400MHz,CDCl 3 ):12.4(s,1H),7.30-7.18(m,15H),0.98(s,9H).
Example 4
130.2g (1 mol) of t-butylpyruvic acid and 1200mL of xylene were charged into a reaction flask under a nitrogen atmosphere. Heating to 50-55 deg.C under stirring, slowly adding dropwise dioxane solution containing 280g (1.08 eq) of triphenylmethylamine, and controlling internal temperature at 100-108 deg.C under micro vacuum reflux for water separation for 22 hr, wherein HPLC detection shows that raw material is less than 0.8%. Filtering after the reaction is finished, concentrating the filtrate to remove xylene and dioxane, replacing the xylene and dioxane with methanol, cooling to 15-20 ℃, pulping for 1 hour, and filtering to obtain 324.3g of Schiff base 2-triphenylmethylimino-3, 3-dimethylbutyric acid, wherein the yield is 87.3 percent, and the HPLC purity is 99.7 percent.
The second step: synthesis of racemic D/L-tert-leucine
Example 5
Under the protection of nitrogen, 115g (0.5 mol, 1eq) of 2-tert-butoxycarbonylimino-3, 3-dimethylbutyric acid and 600mL of ethanol are added into a reaction bottle, the temperature is reduced to 0-5 ℃, 30.3g (0.8mol, 1.6 eq) of sodium borohydride is added in batches within 2 hours, the reaction is carried out for 2 hours at the temperature of 0-5 ℃, the reaction is slowly heated to room temperature for 2 hours, sampling TLC detects that no raw material is left, and the ethanol is removed by decompression and concentration. Adding 1000mL of 2-methyltetrahydrofuran and 300mL of water, adding hydrobromic acid to adjust the pH value to be 6-7, standing to separate an aqueous phase and collect an organic phase, adding 100mL of water to the extracted organic phase, heating to 25-35 ℃, adding a hydrobromic acid solution to adjust the pH value to be 1-2, stirring to react for 2 hours, removing the protection by TLC detection, cooling the organic phase to be 5-10 ℃, adding 2M sodium hydroxide to adjust the pH value to be 12-12.5, standing to separate the organic phase and collect an aqueous phase, adding a hydrobromic acid solution to adjust the pH value to be 5.9-6.2 to the aqueous phase, stirring at room temperature, separating out a large amount of solids, filtering, rinsing with a small amount of deionized water, and drying to obtain 54.9g of racemic D/L-tertiary leucine, wherein the yield is 83.7%, the HPLC purity is 99.5%, the external standard content is 98.7%, and the solubility is qualified.
Example 6
Under nitrogen protection, 185.8g (0.5 mol, 1eq) of 2-triphenylmethylimino-3, 3-dimethylbutyric acid and 900mL of isopropanol were charged into a reaction flask. Cooling to 0-5 deg.C, adding 12g (0.55mol, 1.1eq) of lithium borohydride in 2 hr, reacting at 0-5 deg.C for 2 hr, slowly heating to room temperature, reacting for 0.5 hr, sampling, detecting by TLC, adding hydrobromic acid solution to adjust pH to 6-7, and concentrating under reduced pressure to remove isopropanol. Adding 1000mL of tetrahydrofuran and 200mL of water, filtering, standing the filtrate to separate out a water phase and collecting an organic phase, adding 100mL of water into the extracted organic phase, heating to 25-35 ℃, adding a hydrobromic acid solution to adjust the pH =1-2, reacting for 2 hours, detecting by TLC (thin-layer chromatography) to protect and remove the organic phase, cooling to 5-10 ℃, adding 2M sodium hydroxide to adjust the pH to be more than 12, standing to separate out the organic phase, collecting the water phase, adjusting the pH of the water phase to =5.9-6.2 by the hydrobromic acid, stirring at room temperature, separating out a large amount of solid, filtering, rinsing by a small amount of deionized water and n-heptane, drying to obtain 58.4g of racemic D/L-tert-leucine, wherein the yield is 89.1%, the HPLC purity is 99.3%, the external standard content is 98.6%, and the solubility is qualified.
Example 7
Under the protection of nitrogen, 185.8g (0.5mol, 1eq) of 2-triphenylmethylimino-3, 3-dimethylbutyric acid and 800mL of ethanol are added into a reaction bottle, the temperature is reduced to 0-5 ℃, 34.1g (0.9mol, 1.8eq) of sodium borohydride is added in batches within 2 hours, the temperature is controlled to be 0-5 ℃, the reaction is carried out for 2 hours, the temperature is slowly raised to room temperature for reaction for 0.5 hour, sampling TLC (thin layer chromatography) is carried out to detect that no raw material remains, 4M hydrochloric acid is added to adjust the pH value to be 6-7, and the ethanol is removed by decompression and concentration. Adding 1000mL of 2-methyltetrahydrofuran and 200mL of water, filtering, standing the filtrate to separate out a water phase and collect an organic phase, adding 100mL of water into the extracted organic phase, heating to 25-35 ℃, adding 4M hydrochloric acid to adjust the pH to be =1-2, stirring for reacting for 2 hours, detecting by TLC to protect and remove, cooling the organic phase to 5-10 ℃, adding 2M potassium hydroxide to adjust the pH to be =11-12, standing to separate out the organic phase and collect the aqueous phase, adjusting the pH of the aqueous phase to be =5.9-6.2 by 4M hydrochloric acid, stirring at room temperature, separating out a large amount of solid, adding 2-methyltetrahydrofuran to extract 500mL of liquid, extracting twice, combining the organic phases, concentrating the organic phase to a non-flowing liquid, adding a small amount of deionized water and 200mL of n-heptane to pulp, filtering, drying to obtain 60.2g of racemic D/L-tert-leucine, the yield is 91.8%, the purity is 99.6%, the external standard content is 99.0%, and the solubility is qualified.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (6)
1. A method for preparing racemic D/L-tert-leucine is characterized in that the reaction equation is as follows:
the method comprises the following steps:
the first step is as follows: condensation reaction
Reacting trimethylpyruvic acid with NH 2 Dissolving P in an organic solvent, adding a catalyst, heating, carrying out water-separation condensation to generate Schiff base; the NH 2 -P is selected from NH 2 Boc or NH 2 Tr, the organic solvent is selected from toluene, dioxane, xylene or a mixture of the toluene, the dioxane and the xylene in any proportion, and the catalyst is selected from anhydrous ketone sulfate or p-toluenesulfonic acid;
the second step is that: reduction and deprotection
Dissolving the Schiff base obtained in the first step in an organic solvent, adding a reducing agent for reaction, carrying out acidolysis deprotection, adding a base for adjusting to an isoelectric point, and obtaining racemic D/L-tert-leucine; and when deprotection is carried out, acid is selected from hydrochloric acid or hydrobromic acid.
2. The process for producing racemic D/L-tert-leucine according to claim 1, characterized in that: in the first step, the mass ratio of the trimethylpyruvic acid to the catalyst is 1.1-0.05; trimethylpyruvic acid and NH 2 -P molar ratio 1.05-1.12.
3. The process for producing racemic D/L-tert-leucine according to claim 1, characterized in that: in the second step, the reducing agent is selected from sodium borohydride or lithium borohydride.
4. The process for producing racemic D/L-tert-leucine according to claim 1, characterized in that: in the second step, the reducing agent is added in a molar amount of 1.0-2.0 of trimethylpyruvic acid.
5. The process for producing racemic D/L-tert-leucine according to claim 1, characterized in that: in the second step, the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.
6. The process for producing racemic D/L-tert-leucine according to claim 1, characterized in that: in the second step, the alkali is selected from potassium hydroxide, potassium carbonate, sodium hydroxide or sodium carbonate; isoelectric point pH =5.9-6.2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010083292.5A CN111233685B (en) | 2020-02-09 | 2020-02-09 | Preparation method of racemic D/L-tert-leucine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010083292.5A CN111233685B (en) | 2020-02-09 | 2020-02-09 | Preparation method of racemic D/L-tert-leucine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111233685A CN111233685A (en) | 2020-06-05 |
| CN111233685B true CN111233685B (en) | 2023-01-10 |
Family
ID=70873027
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010083292.5A Active CN111233685B (en) | 2020-02-09 | 2020-02-09 | Preparation method of racemic D/L-tert-leucine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111233685B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3917835A1 (en) * | 1989-06-01 | 1990-12-20 | Hoechst Ag | 3,3,3-Tri:fluoro-alanine prodn. from tri:fluoro-pyruvic acid and amide - dehydrating product to acyl-imine, reaction with tin chloride, then hydrolysing and new process intermediates, useful as enzyme inhibitor |
| CN105237406A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Synthesis method of (R)-(-)-1-methyl-3-amphetamine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8133717B2 (en) * | 2006-12-22 | 2012-03-13 | Richmond Chemical Corporation | Stereoinversion of amino acids in a single reactor |
-
2020
- 2020-02-09 CN CN202010083292.5A patent/CN111233685B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3917835A1 (en) * | 1989-06-01 | 1990-12-20 | Hoechst Ag | 3,3,3-Tri:fluoro-alanine prodn. from tri:fluoro-pyruvic acid and amide - dehydrating product to acyl-imine, reaction with tin chloride, then hydrolysing and new process intermediates, useful as enzyme inhibitor |
| CN105237406A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Synthesis method of (R)-(-)-1-methyl-3-amphetamine |
Non-Patent Citations (2)
| Title |
|---|
| Evolution of eukaryal tRNA-guanine transglycosylase: insight gained from the heterocyclic substrate recognition by the wild-type and mutant human and Escherichia coli tRNA-guanine transglycosylases;Yi-Chen Chen等;《Nucleic Acids Research》;20101203;第39卷(第7期);第2834-2844页 * |
| Trifluoroalanine iV-Carboxy Anhydride: A Reactive Intermediate for the Synthesis of Low Surface Energy Polypeptides;E. Dessipri等;《Macromolecules》;19941231;第27卷(第19期);第5463-5470页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111233685A (en) | 2020-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113999142B (en) | Preparation method of chiral N-Boc-trans-1, 2-cyclohexanediamine | |
| EP0441160B1 (en) | Process for preparing levo and dextro fenfluramine | |
| CN115160158A (en) | Preparation method of chiral tert-leucinol | |
| WO2012004391A1 (en) | Process for the preparation of flupirtine maleate | |
| US7355080B2 (en) | Method of preparing memantine hydrochloride | |
| CN109824545B (en) | Preparation method of trans-4-N-Boc-aminocyclohexane carboxylic acid | |
| CN111170878B (en) | Method for preparing D-type or L-type tert-leucine | |
| CN111233685B (en) | Preparation method of racemic D/L-tert-leucine | |
| CN112608243A (en) | Synthesis method of trans-3-aminobutanol | |
| CN112876502B (en) | Preparation method of N-trimethylsiloxyethoxycarbonyl-N-methyl-L/D-leucine | |
| DK170331B1 (en) | Process for the preparation of rimantadine | |
| CN113461538A (en) | Preparation method of 2-chloro-3-bromoaniline | |
| CN109879780B (en) | Preparation method of (2-methylamine-ethyl) -tert-butyl carbamate | |
| Effenberger et al. | Amino acids; 13: Investigations on the synthesis of DL-serine from α-haloacrylic acid derivatives | |
| CN114213283A (en) | Method for preparing [2- [1- (Fmoc-amino) ethoxy ] acetic acid by one-pot method | |
| JP4190879B2 (en) | A novel intermediate for the production of theanine | |
| CN112125864B (en) | Synthesis method of 1,1 '-diamino-5, 5' -bitetrazole | |
| CN111116430A (en) | Preparation method of sodium taurate | |
| JPH07138210A (en) | Production of aminopropane derivative | |
| EP0065867B1 (en) | Optical resolution of dl-cysteine | |
| CN113603604B (en) | Preparation method of tert-butyl glycinate | |
| CN114853619B (en) | Preparation method of N-methyltyramine hydrochloride suitable for industrial production | |
| JPH06199747A (en) | Production of l-alaninol | |
| CN113173860B (en) | Preparation method of 2-methylalanine | |
| CN110835319B (en) | Synthesis method of benazepril intermediate and benazepril hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20231008 Address after: 730030 Production Management Building (Room 310), Zone B, Specialized and Special New Chemical Industry Incubation Base, No. 751 Qiyunshan Road, Lanzhou New Area, Lanzhou City, Gansu Province Patentee after: Gansu Huijian Pharmaceutical Co.,Ltd. Address before: Toulong village, Binhuai Town, Binhai County, Yancheng City, Jiangsu Province Patentee before: BINHAI HANHONG BIOCHEMICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right |