CN111170878B - Method for preparing D-type or L-type tert-leucine - Google Patents
Method for preparing D-type or L-type tert-leucine Download PDFInfo
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- CN111170878B CN111170878B CN202010083291.0A CN202010083291A CN111170878B CN 111170878 B CN111170878 B CN 111170878B CN 202010083291 A CN202010083291 A CN 202010083291A CN 111170878 B CN111170878 B CN 111170878B
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- 238000000034 method Methods 0.000 title claims abstract description 20
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000002262 Schiff base Substances 0.000 claims abstract description 12
- 150000004753 Schiff bases Chemical class 0.000 claims abstract description 12
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- -1 tert-butyl Grignard reagent Chemical class 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 claims abstract description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- 238000010438 heat treatment Methods 0.000 claims description 13
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 claims description 8
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 7
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- HUWOELPKRRQCMG-UHFFFAOYSA-L [Cl-].[Li+].C(C)(C)(C)[Mg]Br Chemical group [Cl-].[Li+].C(C)(C)(C)[Mg]Br HUWOELPKRRQCMG-UHFFFAOYSA-L 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- CQUDQIHOOFVPBZ-UHFFFAOYSA-L [Cl-].[Li+].[Cl-].C(C)(C)(C)[Mg+] Chemical compound [Cl-].[Li+].[Cl-].C(C)(C)(C)[Mg+] CQUDQIHOOFVPBZ-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- TYEYBOSBBBHJIV-UHFFFAOYSA-M 2-oxobutanoate Chemical compound CCC(=O)C([O-])=O TYEYBOSBBBHJIV-UHFFFAOYSA-M 0.000 claims description 3
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical group CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 3
- WDPZTIFGRQKSEN-UHFFFAOYSA-N tert-butyl 2-oxoacetate Chemical compound CC(C)(C)OC(=O)C=O WDPZTIFGRQKSEN-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- NPDBDJFLKKQMCM-BYPYZUCNSA-N (2r)-2-azaniumyl-3,3-dimethylbutanoate Chemical compound CC(C)(C)[C@@H]([NH3+])C([O-])=O NPDBDJFLKKQMCM-BYPYZUCNSA-N 0.000 description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 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 description 2
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 2
- JOUNXZVZNLKLGN-OAHLLOKOSA-N C(C)(=O)OC(C=N[S@](=O)C(C)(C)C)(C)C Chemical compound C(C)(=O)OC(C=N[S@](=O)C(C)(C)C)(C)C JOUNXZVZNLKLGN-OAHLLOKOSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- AXAZMDOAUQTMOW-UHFFFAOYSA-N dimethylzinc Chemical compound C[Zn]C AXAZMDOAUQTMOW-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- LHRZWPOUDWONOM-UHFFFAOYSA-N 2-tert-butylsulfinyliminoacetic acid Chemical compound CC(C)(C)S(=O)N=CC(O)=O LHRZWPOUDWONOM-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CHPAJOSJONRYPT-CYBMUJFWSA-N ethyl 2-[(r)-tert-butylsulfinyl]iminoacetate Chemical compound CCOC(=O)C=N[S@](=O)C(C)(C)C CHPAJOSJONRYPT-CYBMUJFWSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 229960002935 telaprevir Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
-
- 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
- C07C227/12—Formation of amino and carboxyl groups
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a method for preparing D-type or L-type tert-leucine, belonging to the technical field of organic synthesis. The first step is as follows: glyoxylate is taken as a raw material and condensed with chiral tert-butyl sulfinamide to obtain Schiff base; the second step is that: schiff base reacts with tert-butyl Grignard reagent and catalyst at low temperature, and then is hydrolyzed under acid/alkali conditions to obtain D-type or L-type tert-leucine. The method is simple and convenient to operate, high in reaction yield, high in purity and content of the obtained product more than 99%, less than 0.2% of single impurity, more than or equal to 98.5% of chiral purity, and has potential process amplification prospect.
Description
Technical Field
The invention relates to the field of chiral amino acid preparation, and in particular relates to a method for preparing D-type or L-type tert-leucine.
Background
D-tert-Leucine, english name D-tert-Leucine, CAS:26782-71-8; L-tert-Leucine, english name L-tert-Leucine, CAS:20859-02-3. The two amino acids are both non-natural amino acids, and have special steric hindrance and hydrophobicity, so that the two amino acids can be widely applied in chemistry and biology, wherein the D-tert-leucine can be used as a chiral resolution reagent and a medical intermediate; l-tert-leucine can be used as an intermediate of telaprevir and is widely used for synthesizing polypeptide medicaments.
The derivative of D-type or L-type tertiary leucine can be used as an asymmetric template for inducing asymmetry in asymmetric synthesis, and the modification of the derivative on the polypeptide drug can improve the drug effect of the polypeptide drug.
Because the existing synthesis method mainly adopts a method of salifying and splitting the tert-leucine racemate and the tartaric acid, and the operation is relatively complicated, a new synthesis method needs to be developed to realize the simultaneous effective preparation of the two configurations.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a method for preparing D-type or L-type tert-leucine. The first step is as follows: taking glyoxylate as a raw material, and condensing with R-type or S-type tert-butyl sulfinamide to obtain Schiff base; the second step is that: schiff base reacts with Grignard reagent and catalyst under low temperature condition, and then is hydrolyzed under acid/alkali condition to obtain D-type or L-type tert-leucine. The method is simple and convenient to operate, high in reaction yield, high in purity and content of the obtained product more than 99%, less than 0.2% of single impurity, more than or equal to 98.5% of chiral purity, and has potential process amplification prospect.
A method for preparing D-type or L-type tert-leucine is completed through two-step reaction, and specifically comprises the following steps:
the first step is as follows: condensation reaction
Adding glyoxylic ester and chiral tert-butyl sulfinamide into an organic solvent, and heating, dehydrating and condensing under the catalysis of pyrrolidine to generate Schiff base;
the second step is that: nucleophilic addition and hydrolysis
Dissolving the Schiff base obtained in the first step in an organic solvent, adding a tert-butyl Grignard reagent at low temperature for reaction, deprotecting by acid, adding a base for hydrolysis, adding an acid, and adjusting to an isoelectric point to obtain D-type or L-type tert-leucine.
The reaction equation is expressed as follows:
further, in the above technical solution, the glyoxylic acid ester in the first step is selected from methyl glyoxylate, ethyl glyoxylate or tert-butyl glyoxylate.
Further, in the above technical solution, the organic solvent in the first step is selected from toluene, dioxane or tetrahydrofuran.
Further, in the above technical scheme, in the first step, the molar ratio of the glyoxylic ester to the chiral tertiary-butyl sulfinamide is 1.
Further, in the above technical solution, the t-butyl grignard reagent in the second step is selected from t-butyl magnesium bromide-lithium chloride or t-butyl magnesium chloride-lithium chloride. Tert-butyl magnesium bromide-lithium chloride is preferred.
Further, in the above technical scheme, the dropping temperature of the Grignard reagent in the second step is selected from-20 ℃ to-60 ℃.
Further, in the above technical scheme, in the second step, a catalyst is added during the nucleophilic addition reaction, and the catalyst is selected from CeCl 3 、LaCl 3 -2LiCl、ZnMe 2 Or ZnEt 2 。
Further, in the above technical scheme, in the second step, the mole ratio of the schiff base, the tert-butyl grignard reagent and the catalyst is 1:1.0-1.5:1.0-1.7.
Further, in the above technical scheme, the acid in the second step is selected from hydrochloric acid or sulfuric acid; the base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
Further, in the above technical scheme, the isoelectric point of the second step is pH =5.9-6.2.
Advantageous effects of the invention
The invention takes glyoxylate as a raw material and is completed by two steps of reactions. The first step is as follows: glyoxylate is taken as a raw material and condensed with chiral tert-butyl sulfinamide to obtain Schiff base; the second step is that: schiff base reacts with tert-butyl Grignard reagent at low temperature, and then D-type or L-type tert-leucine is obtained by hydrolysis under acid/alkali conditions. The method is simple and convenient to operate, high in reaction yield, high in product purity and content of more than 99%, less than 0.2% of single impurity, more than or equal to 98.5% of product chiral purity, and 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 first step is as follows: synthesis of (2-methylpropane-2-sulfinylimino) -acetic acid ester
Example 1
Under nitrogen protection, 88.1g (1 mol) of methyl glyoxylate and 15g of toluene 200mL of tetrahydropyrrole were put into a reaction flask. After stirring uniformly, 118.8g (0.98mol, 0.98eq) of S-tert-butylsulfinamide in toluene was added, the mixture was heated to reflux and water was separated for 2 hours, and the reaction was completed by TLC. After the reaction, the mixture was concentrated to remove toluene and pyrrolidine, and then distilled under reduced pressure to obtain 175g of S- (2-methylpropane-2-sulfinylimino) -acetic acid methyl ester, the yield was 91.5%, and the HPLC purity was 99.1%. 1 HNMR(400MHz,CDCl 3 ):7.92(s,1H),3.67(s,3H),1.16(s,9H).
Example 2
Under the protection of nitrogen, 102.1g (1 mol) of ethyl glyoxylate, 200mL of anhydrous dioxane and 15g of tetrahydropyrrole were put into a reaction flask. After stirring well, 117.6g (0.97mol, 0.97eq) of the solution of S-tert-butylsulfinamide in dioxane was added and the temperature was raised toThe reflux was separated from water for 2.5 hours and the reaction was completed by TLC. After the reaction is finished, the dioxane and the tetrahydropyrrole are removed through concentration, and the S- (2-methylpropane-2-sulfinylimino) -ethyl acetate 186.4g is obtained through reduced pressure distillation, the yield is 90.8 percent, and the HPLC purity is 98.9 percent. 1 HNMR(400MHz,CDCl 3 ):8.10(s,1H),4.21-4.25(m,2H),1.15-1.31(m,12H).
Example 3
Under nitrogen protection, 130.2g (1 mol) of tert-butyl glyoxylate, tetrahydropyrrole (18 g) and tetrahydrofuran (400 mL) were placed in a reaction flask. After stirring, 117.6g (0.97mol, 0.97eq) of tetrahydrofuran solution of R-tert-butylsulfinamide was added, the mixture was heated to reflux for 11 hours, and the reaction was completed by TLC. After the reaction, tetrahydrofuran and tetrahydropyrrole are removed by concentration, and R- (2-methylpropane-2-sulfinylimino) -tert-butyl acetate 205.1g is obtained by reduced pressure distillation, the yield is 87.9 percent, and the HPLC purity is 98.9 percent. 1 HNMR(400MHz,CDCl 3 ):7.92(s,1H),1.18(s,9H),1.16(s,9H).
The second step is that: synthesis of D-or L-form of tert-leucine
Example 4
Under nitrogen protection, 95.6g (0.5 mol) of S- (2-methylpropane-2-sulfinylimino) -acetic acid methyl ester and 500mL of dichloromethane were charged into a reaction flask. Cooling to-20 deg.C, slowly adding mixed solution of pre-prepared 1.5eq 2.0M tert-butyl magnesium bromide-lithium chloride (preparation method refers to i-PrMgCl-LiCl)/tetrahydrofuran solution and 1.7eq diethyl zinc, reacting at-20 deg.C for 1 hr, slowly heating to 0 deg.C, stirring for 2 hr, sampling HPLC to detect raw material less than 0.5% AN, adding saturated NH 4 Aqueous solution of Cl, ethyl acetate extraction and saturated sodium chloride washing. Heating the organic phase to 30-35 deg.C, slowly adding 1.1eq 4.0M hydrogen chloride/ethyl acetate solution, after the dropwise addition, slowly reducingHeating to 0-5 deg.C, filtering, rinsing the filter cake with n-heptane, adding the obtained product into tetrahydrofuran, dropwise adding 2.0eq 10% lithium hydroxide aqueous solution, heating to 25-30 deg.C, and reacting for 2 hr. After hydrolysis is completed, the temperature is reduced to 0 ℃, 10% hydrochloric acid is dripped to adjust the pH =5.9-6.2, and a large amount of solid is separated out. Filtration and rinsing of the filter cake with n-heptane gave 55.8g of L-tert-leucine. Yield 85.1%, HPLC purity 99.4%,98.7% ee, external standard content 98.8%, and solubility is acceptable. Under the same conditions, when dimethyl zinc was not added, the L-tert-leucine yield was 84.2%, HPLC purity was 99.5%,88.2% ee.
Example 5
Under the protection of nitrogen, 102.6g (0.5 mol) of S- (2-methylpropane-2-sulfinylimino) -acetic acid ethyl ester and 500mL of dichloromethane were charged into a reaction flask. Cooling to-20 deg.C, slowly adding 1.2eq2.0M tert-butyl magnesium chloride-lithium chloride/2-methyltetrahydrofuran solution and 1.5eq mixed solution of dimethyl zinc, reacting at-20 deg.C for 1 hr, slowly heating to 0 deg.C, stirring for 2 hr, sampling HPLC to determine raw material content less than 0.5% AN, adding saturated NH 4 Aqueous solution of Cl, ethyl acetate extraction and saturated sodium chloride washing. Keeping the organic phase, heating to 30-35 ℃, slowly dropping 1.1eq 4.0M hydrogen chloride/ethyl acetate solution, slowly cooling to 0-5 ℃ after dropping, filtering, rinsing filter cake with n-heptane, putting the obtained product into 2-methyltetrahydrofuran, dropping 2.0eq 10% sodium hydroxide aqueous solution, heating to 25-30 ℃ and reacting for 2 hours. After the hydrolysis is completed, the temperature is reduced to 0 ℃, 5% dilute sulfuric acid is added dropwise to adjust the pH =5.9-6.2, and a large amount of solid is separated out. Filtration and cake rinsing with n-heptane yielded 55.8g of L-tert-leucine. Yield 84.3%, HPLC purity 99.2%,98.9% ee, external standard content 98.5%, and solubility was acceptable.
Example 6
Under the protection of nitrogen, 116.7g (0.5 mol) of R- (2-methylpropane-2-sulfinylimino) -tert-butyl acetate and 600mL of dichloromethane were charged into a reaction flask. Cooling to-60 deg.C, slowly adding prepared 1.5eq 2.0M tert-butyl magnesium bromide-lithium chloride/tetrahydrofuran solution and 1.1eq CeCl 3 Mixing the solutions, reacting at-20 deg.C for 1 hr, sampling HPLC detecting raw material < 0.5% 4 Aqueous solution of Cl, ethyl acetate extraction and saturated sodium chloride washing. Keeping the organic phase, heating to 30-35 ℃, slowly dropping 1.1eq 4.0M hydrogen chloride/ethyl acetate solution, slowly cooling to 0-5 ℃ after dropping, filtering, rinsing filter cakes with n-heptane, putting the obtained product into 2-methyltetrahydrofuran, dropping 2.0eq 10% potassium hydroxide aqueous solution, heating to 25-30 ℃ and reacting for 2 hours. After hydrolysis is completed, the temperature is reduced to 0 ℃, 10% hydrochloric acid is dripped to adjust the pH =5.9-6.2, and a large amount of solid is separated out. Filtration and cake rinsing with n-heptane gave 56.7g of D-tert-leucine. Yield 86.5%, HPLC purity 99.5%,99.1% ee, external standard content 98.7%, and solubility is acceptable.
Example 7
Under the protection of nitrogen, 102.6g (0.5 mol) of R- (2-methylpropane-2-sulfinylimino) -acetic acid ethyl ester and 500mL of dichloromethane are put into a reaction bottle. Cooling to-60 deg.C, slowly adding prepared 1.5eq 2.0M tert-butyl magnesium chloride-lithium chloride/tetrahydrofuran solution and 1.2eq LaCl 3 -2LiCl, reacting at-20 deg.C for 1 hr, sampling HPLC detecting raw material < 0.5%AN, adding saturated NH 4 Aqueous solution of Cl, ethyl acetate extraction and saturated sodium chloride washing. Keeping the organic phase, heating to 30-35 ℃, slowly dripping 1.1eq 4.0M hydrogen chloride/ethyl acetate solution, slowly cooling to 0-5 ℃ after dripping, filtering, rinsing filter cakes by using n-heptane, putting the obtained product into 2-methyltetrahydrofuran, dripping 2.0eq 10% lithium hydroxide aqueous solution, heating to 25-30 ℃ and reacting for 2 hours. After complete hydrolysis, coolingWhen the pH of the solution was adjusted to 5.9 to 6.2 by adding 10% hydrochloric acid dropwise to 0 ℃, a large amount of solid precipitated. Filtration and cake rinsing with n-heptane yielded 56.1g of D-tert-leucine. The yield was 85.5%, the HPLC purity was 99.6%,98.5% ee, the external standard content was 98.8%, and the solubility was acceptable.
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 (7)
1. A process for the preparation of D-or L-form of tert-leucine, comprising the steps of:
the first step is as follows: condensation reaction
Adding glyoxylic ester and chiral tert-butyl sulfinamide into an organic solvent, and heating, dehydrating and condensing under the catalysis of pyrrolidine to generate Schiff base; the glyoxylic ester is selected from methyl glyoxylate, ethyl glyoxylate and tert-butyl glyoxylate;
the second step is that: nucleophilic addition and hydrolysis
Dissolving the Schiff base obtained in the first step in an organic solvent, adding a tert-butyl Grignard reagent at a low temperature for reaction, deprotecting by acid, adding a base for hydrolysis, adding an acid, and adjusting to an isoelectric point to obtain D-type or L-type tert-leucine; the tert-butyl Grignard reagent is selected from tert-butyl magnesium bromide-lithium chloride or tert-butyl magnesium chloride-lithium chloride; adding a catalyst during the nucleophilic addition reaction, wherein the catalyst is selected from CeCl 3 、LaCl 3 -2LiCl、ZnMe 2 Or ZnEt 2 。
2. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the first step, the organic solvent is selected from toluene, tetrahydrofuran or dioxane.
3. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the first step, the heating condition is reflux reaction in a corresponding solvent.
4. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the first step, the molar ratio of the glyoxylic ester to the chiral tert-butyl sulfinamide is 1.
5. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the second step, the mole ratio of the Schiff base, the tert-butyl Grignard reagent and the catalyst is 1:1.0-1.5:1.0-1.7.
6. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the second step, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane or a mixed system.
7. The process for producing D-form or L-form tertiary leucine according to claim 1, characterized in that: in the second deprotection step, the acid is selected from hydrochloric acid or sulfuric acid; the base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, and has isoelectric point of pH =5.9-6.2.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000058346A1 (en) * | 1999-03-30 | 2000-10-05 | Sanofi-Synthelabo | N-sulfonyl-dipeptide derivatives, production and use thereof in therapy |
| CN101875615A (en) * | 2009-04-30 | 2010-11-03 | 复旦大学 | Method for preparing tert-leucine with high selectivity |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000058346A1 (en) * | 1999-03-30 | 2000-10-05 | Sanofi-Synthelabo | N-sulfonyl-dipeptide derivatives, production and use thereof in therapy |
| CN101875615A (en) * | 2009-04-30 | 2010-11-03 | 复旦大学 | Method for preparing tert-leucine with high selectivity |
Non-Patent Citations (6)
| Title |
|---|
| Asymmetric Synthesis and Translational Competence of L-r-(1-Cyclobutenyl)glycine;Robert F. Standaert等;《Org. Lett.》;20041231;第6卷(第21期);第3659-3662页 * |
| Enantioselective synthesis of non-proteinogenic 2-arylallyl-aamino acids via Pd/In catalytic cascades;Ronald Grigg等;《Tetrahedron》;20061231;第62卷;第12159-12171页 * |
| Nickel-catalyzed organozinc-induced unexpected 1,3-migration of tert-butyl from sulfur to carbon in N-tert-butanesulfinyl iminoacetates;Xun Sun等;《Tetrahedron Letters》;20081231;第49卷;第6195-6197页 * |
| Remarkable Salt Effect on In-Mediated Allylation of N-tert-Butanesulfinyl Imines in Aqueous Media: Highly Practical Asymmetric Synthesis of Chiral Homoallylic Amines and Isoindolinones;Ming-Hua Xu等;《Org. Lett.》;20081231;第10卷(第6期);第1259-1262页 * |
| Sequential Ruthenium Catalysis for Olefin Isomerization and Oxidation: Application to the Synthesis of Unusual Amino Acids;Marc Liniger等;《J. Am. Chem. Soc.》;20171231;第139卷;第13944-13949页 * |
| tert-Butylsulfinamide;Pfefferkorn, Jeffrey A.等;《e-EROS Encyclopedia of Reagents for Organic Synthesis》;20011231;第1-5页 * |
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