CN114989043A - Synthesis method of boc-L-glutamic acid dimethyl ester - Google Patents
Synthesis method of boc-L-glutamic acid dimethyl ester Download PDFInfo
- Publication number
- CN114989043A CN114989043A CN202210817331.9A CN202210817331A CN114989043A CN 114989043 A CN114989043 A CN 114989043A CN 202210817331 A CN202210817331 A CN 202210817331A CN 114989043 A CN114989043 A CN 114989043A
- Authority
- CN
- China
- Prior art keywords
- glutamic acid
- boc
- isopropanol
- methanol
- synthesis method
- 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.)
- Pending
Links
- QNSPKWUAZQIIGZ-QMMMGPOBSA-N dimethyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate Chemical compound COC(=O)CC[C@@H](C(=O)OC)NC(=O)OC(C)(C)C QNSPKWUAZQIIGZ-QMMMGPOBSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 96
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 92
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 80
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229960002989 glutamic acid Drugs 0.000 claims abstract description 46
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000007864 aqueous solution Substances 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000243 solution Substances 0.000 abstract description 19
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 239000002253 acid Substances 0.000 abstract description 6
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 6
- 239000003595 mist Substances 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 239000002912 waste gas Substances 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 description 8
- 239000012467 final product Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- 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
- C07C269/04—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 from amines with formation of carbamate 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
- C07C227/14—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
-
- 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 synthesis method of boc-L-glutamic acid dimethyl ester, belonging to the technical field of organic synthesis. The synthesis method comprises the following steps: reacting L-glutamic acid with methanol in the presence of p-toluenesulfonic acid until the L-glutamic acid is completely reacted, removing residual methanol, adding an isopropanol aqueous solution, adjusting the pH value to 7-8, and then adding boc anhydride for reaction to generate boc-L-glutamic acid dimethyl ester. The method does not use reagents of acyl chloride, does not generate volatile acid mist, and treats waste gas and waste water solution in the synthetic process; and the synthesis of the product is completed by a one-pot method, so that the yield is high, the purity is good, and the comprehensive cost is low.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of boc-L-glutamic acid dimethyl ester.
Background
At present, the preparation method of boc-L-glutamic acid dimethyl ester generally adopts the following methods:
in the first method, acetyl chloride (5mL) was slowly added dropwise to methanol (100mL) at 0 ℃ and stirred for 5 minutes.
L-glutamic acid (10g, 67.9mmol) was then added, stirring was continued and heating was continued to reflux, and the reaction was maintained at reflux temperature for 2 hours.
The reaction was stopped, the solvent was removed under reduced pressure and recrystallized from ether.
The resulting oil was dissolved in THF (150mL), TEA (28.5mL, 203.7mmol) was added dropwise at 0 deg.C, and the mixture was stirred at 0 deg.C for 5 minutes.
Boc-anhydride (17.8g, 81.5mmol) in THF (30mL) was added dropwise and stirred to room temperature for 2.5 h.
After completion of the reaction, the solvent was evaporated under reduced pressure, water (200mL) was added to the residue, and the mixture was extracted from the aqueous phase with DCM (2 × 200mL), the combined organic phases were dried over anhydrous sodium sulfate and then concentrated to obtain a crude product, which was purified by flash chromatography (PE: EA ═ 5: 1) to obtain N-Boc-L-glutamic acid dimethyl ester (17.7g, yield 95.2%) as a colorless oily liquid.
Method two, L-glutamic acid (200g) and MeOH (800mL) were charged to a flask, which was then cooled to-10 ℃. Thionyl chloride (324g) was added dropwise at <10 ℃ and the mixture was stirred at room temperature for 18 h.
The reaction was monitored by LC/MS and ethyl acetate (800mL), Na were added sequentially 2 CO 3 (200g)、H 2 O (200g) and boc-anhydride (280 g).
After stirring at room temperature for 18 hours, the resulting mixture was washed with water (400 mL. times.2), and then diluted with toluene (400 mL).
The organic layer was separated and concentrated in vacuo to give the compound boc-L-glutamic acid dimethyl ester (314g, 84% crude yield).
Method three, L-glutamic acid (10g) was dissolved in 90 ml MeOH and 40.4g thionyl chloride was added dropwise for 30 minutes while cooling on ice, then stirred overnight and further concentrated.
The residue was redissolved in 150ml of MeOH, added with 44.7g of triethylamine and 16.3g of boc-anhydride and then added to the ice bath, followed by stirring for 6 hours.
The reaction solution was concentrated, extracted with ethyl acetate, and the organic layer was washed with 10% citric acid and saturated NaHCO 3 And washing with brine。
After drying over sodium sulfate, purification was carried out by silica gel column chromatography to obtain 17.8g (95%) of pale tan oily BOC-L-glutamic acid dimethyl ester.
That is, most of the existing methods are to react L-glutamic acid with thionyl chloride for esterification and then react with boc-anhydride, an acyl chloride reagent is used in the synthetic process to generate volatile acid mist, and the post-treatment is complicated, which is not beneficial to industrial production.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a synthesis method of boc-L-glutamic acid dimethyl ester, which aims to solve the technical problem.
The application can be realized as follows:
in a first aspect, the present application provides a method for synthesizing boc-L-glutamic acid dimethyl ester, which comprises the following steps: reacting L-glutamic acid with methanol in the presence of p-toluenesulfonic acid until the L-glutamic acid is completely reacted, removing residual methanol, adding an isopropanol aqueous solution, adjusting the pH value to 7-8, and then adding boc anhydride for reaction to generate boc-L-glutamic acid dimethyl ester.
In an alternative embodiment, the molar ratio of L-glutamic acid, methanol, and p-toluenesulfonic acid is, in order, 1:1 to 1.3:10 to 13.
In a preferred embodiment, the molar ratio of L-glutamic acid, methanol and p-toluenesulfonic acid is, in order, 1:1 to 1.3:10 to 12.
In an alternative embodiment, L-glutamic acid is reacted with methanol at 25-30 ℃ for 1.5-2.5 h.
In a preferred embodiment, L-glutamic acid is reacted with methanol at 25-30 ℃ for 2 h.
In alternative embodiments, the mass ratio of L-glutamic acid to water in the aqueous isopropanol solution is 1: 3-4;
wherein the isopropanol aqueous solution is obtained by mixing water and isopropanol according to the volume ratio of 2-11: 1.
In a preferred embodiment, the mass ratio of L-glutamic acid to water in the aqueous isopropanol solution is 1: 3.4; the isopropanol water solution is prepared by mixing water and isopropanol according to the volume ratio of 5: 1.
In an alternative embodiment, the pH is adjusted with ammonia.
In an alternative embodiment, the molar ratio of L-glutamic acid to total boc anhydride is 1:1 to 1.3.
In a preferred embodiment, the molar ratio of L-glutamic acid to total boc anhydride is 1:1 to 1.2.
In an alternative embodiment, the boc anhydride is added in 4-6 portions and in equal amounts.
In a preferred embodiment, the boc anhydride is added in 5 portions.
In an alternative embodiment, the reaction is carried out at 25-30 ℃ for 5.5-6.5h after addition of the boc anhydride.
In a preferred embodiment, the reaction is carried out for 6h at 25 to 30 ℃ after the addition of the boc anhydride.
In an alternative embodiment, the method further comprises: and (3) carrying out solid-liquid separation on the system after the boc anhydride reaction is finished, and then rinsing the separated solid.
In an alternative embodiment, the rinsing liquid used for rinsing is isopropanol.
The beneficial effect of this application includes:
according to the synthesis method of boc-L-dimethyl glutamate, no acyl chloride reagent is used in the whole process, volatile acid mist is not brought, waste gas and waste water solution treatment are avoided, the synthesis of the product is completed through a one-pot method, the yield is high, and the purity is good; the isopropanol water solution can effectively remove organic impurities, the purity of the final product is high, the p-toluenesulfonic acid can be recycled, and the comprehensive cost is low.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is an HPLC chromatogram of the synthesized product in the example.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
The following is a specific description of the synthesis method of boc-L-glutamic acid dimethyl ester provided by the present application.
Based on the problems that volatile acid mist is generated due to the use of an acyl chloride reagent in the current synthesis process of boc-L-dimethyl glutamate and the aftertreatment is more complicated, the inventor creatively provides a novel synthesis method of boc-L-dimethyl glutamate, which comprises the following steps:
reacting L-glutamic acid with methanol in the presence of p-toluenesulfonic acid until the L-glutamic acid is completely reacted, removing residual methanol, adding an isopropanol aqueous solution, adjusting the pH value to 7-8, and then adding boc anhydride for reaction to generate boc-L-glutamic acid dimethyl ester.
The corresponding synthetic route is as follows:
alternatively, the molar ratio of L-glutamic acid, methanol, and p-toluenesulfonic acid may be 1:1 to 1.3:10 to 13 in this order, such as 1:1:10, 1:1:11, 1:1:12, 1:1:13, 1:1.1:10, 1:1.1:11, 1:1.1:12, 1:1.1:13, 1:1.2:10, 1:1.2:11, 1:1.2:12, 1:1.2:13, 1:1.3:10, 1:1.3:11, 1:1.3:12, or 1:1.3:13, or may be any other value within the range of 1:1 to 1.3:10 to 13.
In some preferred embodiments, the molar ratio of L-glutamic acid, methanol, and p-toluenesulfonic acid is, in order, 1:1 to 1.3:10 to 12.
More preferably, the molar ratio of L-glutamic acid, methanol and p-toluenesulfonic acid is 1:1.2:12 in sequence.
Under the condition of the mixture ratio, higher yield can be obtained at lower cost, and the economic benefit is high.
In this application, the reaction of L-glutamic acid with methanol is carried out at 25 to 30 ℃ C (room temperature is understood to be) for 1.5 to 2.5 hours.
Specifically, the reaction temperature of L-glutamic acid and methanol may be 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ or 30 ℃ or any other value within the range of 25-30 ℃.
The reaction time of L-glutamic acid and methanol may be 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h, or the like, or may be any other value within a range of 1.5 to 2.5 h.
In some preferred embodiments, L-glutamic acid is reacted with methanol at 25-30 ℃ for 2 h.
In the present application, the methanesulfonic acid functions as a catalyst, and higher yield and purity can be obtained than other catalyst substances.
In the present application, the principle and specific operation of the method for determining whether the reaction of L-glutamic acid is complete can be determined by TLC method, and reference is made to the related prior art, which is not described herein in detail.
And after the L-glutamic acid is reacted, recovering the residual methanol.
Further, an aqueous isopropanol solution was added to remove impurities during the synthesis.
Specifically, water may be added first, followed by isopropanol.
For reference, the mass ratio of L-glutamic acid to water in the aqueous isopropanol solution may be 1:3 to 4, such as 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, or 1:4, and may be any other value within the range of 1:3 to 4.
Wherein the isopropanol aqueous solution is prepared by mixing water and isopropanol at a volume ratio of 2-11:1 (such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or 11: 1).
In some preferred embodiments, the mass ratio of L-glutamic acid to water in the aqueous isopropanol solution is 1: 3.4; the isopropanol water solution is prepared by mixing water and isopropanol according to the volume ratio of 5: 1.
Under the proportion, the purity and the cost of the final product can reach the comprehensive optimal effect.
In the application, ammonia water can be used for adjusting the pH value, and boc acid anhydride is added under the condition that the pH value is 7-8 for further reaction.
For reference, the molar ratio of L-glutamic acid to total boc anhydride may be 1:1 to 1.3, such as 1:1, 1:1.05, 1:1, 1:1.15, 1:2, 1:1.25, 1:3, etc., or may be any other value within the range of 1:1 to 1.3.
In some preferred embodiments, the molar ratio of L-glutamic acid to total boc anhydride is 1:1 to 1.2.
More preferably, the molar ratio of L-glutamic acid to total boc anhydride is 1: 1.2.
It should be noted that, when adding the boc anhydride, the boc anhydride is added in 4 to 6 times (e.g., 4 times, 5 times or 6 times) and the amount of each addition is equal.
By the mode of adding in batches, the temperature in the reaction process can be effectively maintained at 25-30 ℃, and large amount of heat generated after adding a large amount of boc anhydride at one time is avoided, which is not beneficial to obtaining boc-L-dimethyl glutamate.
In some preferred embodiments, the boc anhydride is added in 5 portions.
After adding the boc anhydride, the whole reaction system is reacted for 5.5 to 6.5 hours, such as 5.5 hours, 5.6 hours, 5.7 hours, 5.8 hours, 5.9 hours, 6 hours, 6.1 hours, 6.2 hours, 6.3 hours, 6.4 hours or 6.5 hours, etc., at the temperature of between 25 and 30 ℃ (room temperature), and other arbitrary values in the range of 5.5 to 6.5 hours can be also achieved.
In some preferred embodiments, the reaction is carried out for 6h after addition of the boc anhydride at 25-30 ℃.
Further, the system after the completion of the boc acid anhydride reaction was subjected to solid-liquid separation, and then the separated solid was rinsed.
Wherein, the solid-liquid separation can be carried out by adopting a filtration mode.
The rinsing liquid used for rinsing is isopropanol, and the dosage of the isopropanol is equal to that of the isopropanol in the isopropanol aqueous solution.
Impurities are removed by adopting an isopropanol water solution, and the purity of the final product can reach 99.9 percent at most after the final product is rinsed by isopropanol.
In conclusion, the synthesis method of boc-L-dimethyl glutamate provided by the application does not use reagents such as acyl chloride, does not bring volatile acid mist, does not treat waste gas and waste water solution, completes the synthesis of the product by a one-pot method, and has high yield and good purity; the isopropanol water solution can effectively remove organic impurities, the final product is rinsed by isopropanol, the purity is high, the p-toluenesulfonic acid is recycled, and the comprehensive cost is low.
The features and properties of the present invention are described in further detail below with reference to examples.
Examples
This example provides a method for synthesizing boc-L-glutamic acid dimethyl ester, which comprises the following steps:
(1) 147g L-glutamic acid was added to 384g of methanol;
(2) 198g of p-toluenesulfonic acid is added and reacted for 2 hours at room temperature;
(3) after TLC raw material disappears, recovering methanol;
(4) adding 500ml of water and then 100ml of isopropanol;
(5) adjusting the pH value of the reaction system to 7-8 by using ammonia water;
(6) adding 251g of boc anhydride in 5 times, and reacting at room temperature for 6 hours after the addition is finished;
(7) after the reaction, the mixture was filtered, and the solid was rinsed with 100ml of isopropyl alcohol to obtain 255.5g of boc-L-glutamic acid dimethyl ester.
The HPLC profile of the above synthesized product is shown in FIG. 1, wherein the channel of detector A is 1/200 nm.
The results are shown in Table 1.
TABLE 1 test results
| Peak(s) | Retention time | Area of | Height | Area (%) |
| 1 | 7.728 | 6856 | 10675 | 0.100 |
| 2 | 8.137 | 6843047 | 270389 | 99.813 |
| 3 | 15.006 | 4319 | 6443 | 0.063 |
| 4 | 20.960 | 1645 | 653 | 0.024 |
| Total of | - | 6855867 | 288161 | 100.000 |
That is, the yield of boc-L-glutamic acid dimethyl ester obtained by the above method was 92.8%, and the purity was 99.8%.
Test example 1
This experimental example investigated the effect of different material ratios on the yield and purity of boc-L-glutamic acid dimethyl ester.
Specifically, using the above examples as examples, experimental groups 1 to 6 were set up, in each of which the molar ratios of L-glutamic acid, p-toluenesulfonic acid, methanol, water and boc-anhydride were as shown in Table 2, and the other conditions were the same as in the above examples.
TABLE 2 molar ratios of materials
The results of combining the examples and table 2 can be found:
with the increase of the dosage of p-toluenesulfonic acid and boc-anhydride which are main raw material catalysts, the yield of boc-L-glutamic acid dimethyl ester is gradually increased and does not obviously change after reaching 1.2mol times, and the ratio of L-glutamic acid: p-toluenesulfonic acid: methanol: boc-anhydride molar ratio of 1:1-1.3: 10-12: 1 to 1.2 is preferable.
Test example 2
This test example investigated the effect of different amounts of isopropanol in the isopropanol-water system on the yield and purity of boc-L-glutamic acid dimethyl ester.
Specifically, using the above examples as examples, experimental groups 7 to 10 were set, and the volume ratio of isopropanol to water in the isopropanol aqueous solution in each group is shown in table 3, and the other conditions were the same as in the above examples.
TABLE 3 volume ratio of isopropyl alcohol to water
The results of combining the examples and table 3 can be found:
the mixed solvent of water and isopropanol can effectively remove impurities in the synthesis process, the purity of the final product after rinsing with isopropanol can reach 99.9 percent at most, and the proportion of water to propanol is kept between 5:1 is preferred.
Test example 3
This experimental example investigated the effect of different catalysts on the yield and purity of boc-L-glutamic acid dimethyl ester.
Specifically, using the above examples as examples, experimental groups 11 to 12 were set, and the kind and amount of the catalyst in each group are shown in table 4, and the other conditions were the same as in the above examples.
TABLE 4 type and amount of catalyst
| Group of | Molar ratio of L-glutamic acid to catalyst | Total yield (%) | Purity (%) |
| Experimental group 11 | 1:1.2 | 90.2 | 99.8 |
| Experimental group 12 | 1:1.2 | 57 | 96.3 |
The results of combining the examples and table 4 can be found:
compared with the method using methanesulfonic acid as a catalyst, the method has the advantages that the yield and the product purity of the p-toluenesulfonic acid are better, the mother liquor is recycled, the pH is adjusted to be acidic, the recycled p-toluenesulfonic acid can be obtained after filtration, and the recovery rate is about 90%.
In conclusion, the synthesis method of boc-L-glutamic acid dimethyl ester provided by the application does not use reagents such as acyl chloride, does not bring volatile acid mist, does not treat waste gas and waste water solution, completes the synthesis of the product by a one-pot method, and has high yield and good purity; the isopropanol water solution can effectively remove organic impurities, the final product is rinsed by isopropanol, the purity is high, the p-toluenesulfonic acid is recycled, and the comprehensive cost is low.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthesis method of boc-L-glutamic acid dimethyl ester is characterized by comprising the following steps: reacting L-glutamic acid with methanol in the presence of p-toluenesulfonic acid until the L-glutamic acid is completely reacted, removing residual methanol, adding an isopropanol aqueous solution, adjusting the pH value to 7-8, and then adding boc anhydride for reaction to generate boc-L-glutamic acid dimethyl ester.
2. The synthesis method according to claim 1, wherein the molar ratio of the L-glutamic acid to the methanol to the p-toluenesulfonic acid is 1:1 to 1.3:10 to 13 in this order;
preferably, the molar ratio of the L-glutamic acid to the methanol to the p-toluenesulfonic acid is 1:1-1.3:10-12 in sequence.
3. The synthesis method according to claim 1, wherein the L-glutamic acid and the methanol are reacted at 25-30 ℃ for 1.5-2.5 h;
preferably, the L-glutamic acid and the methanol are reacted at 25 to 30 ℃ for 2 h.
4. The synthesis method according to claim 1, wherein the mass ratio of the L-glutamic acid to the water in the isopropanol aqueous solution is 1: 3-4;
wherein the isopropanol aqueous solution is obtained by mixing water and isopropanol according to the volume ratio of 2-11: 1;
preferably, the mass ratio of the L-glutamic acid to the water in the isopropanol aqueous solution is 1: 3.4; the isopropanol aqueous solution is obtained by mixing water and isopropanol according to the volume ratio of 5: 1.
5. The method of claim 1, wherein the pH is adjusted with aqueous ammonia.
6. The synthesis method according to claim 1, wherein the molar ratio of the L-glutamic acid to the total boc anhydride is 1:1 to 1.3;
preferably, the molar ratio of the L-glutamic acid to the total boc anhydride is 1:1 to 1.2.
7. The synthesis method according to claim 6, wherein the boc anhydride is added in 4-6 times with equal amount of each time;
preferably, the boc anhydride is added in 5 portions.
8. The synthesis method of claim 1, wherein the reaction is carried out for 5.5 to 6.5 hours at 25 to 30 ℃ after adding the boc anhydride;
preferably, the reaction is carried out for 6h at 25-30 ℃ after adding the boc anhydride.
9. The method of synthesis of claim 1, further comprising: and (3) carrying out solid-liquid separation on the system after the boc anhydride reaction is finished, and then rinsing the separated solid.
10. The synthesis method according to claim 7, wherein the rinsing liquid used for rinsing is isopropanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210817331.9A CN114989043A (en) | 2022-07-12 | 2022-07-12 | Synthesis method of boc-L-glutamic acid dimethyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210817331.9A CN114989043A (en) | 2022-07-12 | 2022-07-12 | Synthesis method of boc-L-glutamic acid dimethyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114989043A true CN114989043A (en) | 2022-09-02 |
Family
ID=83019187
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210817331.9A Pending CN114989043A (en) | 2022-07-12 | 2022-07-12 | Synthesis method of boc-L-glutamic acid dimethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114989043A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115947670A (en) * | 2022-12-08 | 2023-04-11 | 常州吉恩药业有限公司 | Synthesis process of N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester |
| CN116023302A (en) * | 2022-12-06 | 2023-04-28 | 烟台舜康生物科技有限公司 | Boc-L-glutamic acid dimethyl ester and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1080218A (en) * | 1963-11-12 | 1967-08-23 | Merck & Co Inc | Preparation of ª†-methyl glutamate and ª†-methyl glutanate hydrochloride |
| US4530801A (en) * | 1984-02-27 | 1985-07-23 | Lever Brothers Company | Nopol derived sulfonates |
| CN101333173A (en) * | 2007-06-26 | 2008-12-31 | 齐鲁制药有限公司 | N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN111807994A (en) * | 2020-07-27 | 2020-10-23 | 四川嘉瑛莱科技有限责任公司 | L-glutamic acid derivative and synthesis method and application thereof |
-
2022
- 2022-07-12 CN CN202210817331.9A patent/CN114989043A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1080218A (en) * | 1963-11-12 | 1967-08-23 | Merck & Co Inc | Preparation of ª†-methyl glutamate and ª†-methyl glutanate hydrochloride |
| US4530801A (en) * | 1984-02-27 | 1985-07-23 | Lever Brothers Company | Nopol derived sulfonates |
| CN101333173A (en) * | 2007-06-26 | 2008-12-31 | 齐鲁制药有限公司 | N-[4-(butanal-4-group)-benzoyl]-L-glutamic acid dimethyl ester compound and method for preparing pemetrexed by using the compounds |
| CN105439895A (en) * | 2015-12-30 | 2016-03-30 | 浙江汇能生物股份有限公司 | Preparation method of N (4-aminobenzoyl)-L-glutamic acid |
| CN111807994A (en) * | 2020-07-27 | 2020-10-23 | 四川嘉瑛莱科技有限责任公司 | L-glutamic acid derivative and synthesis method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| P. BIEHL ET AL: "Weak Polyampholytes at the Interface of Magnetic Nanocarriers: A Facile Catch-and-Release Platform for Dyes", 《LANGMUIR》, vol. 36, pages 6095 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116023302A (en) * | 2022-12-06 | 2023-04-28 | 烟台舜康生物科技有限公司 | Boc-L-glutamic acid dimethyl ester and preparation method thereof |
| CN115947670A (en) * | 2022-12-08 | 2023-04-11 | 常州吉恩药业有限公司 | Synthesis process of N-tert-butyloxycarbonyl-L-glutamic acid dimethyl ester |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114989043A (en) | Synthesis method of boc-L-glutamic acid dimethyl ester | |
| CN112739683B (en) | Preparation method of brivaracetam and intermediate thereof | |
| Avenoza et al. | Enantioselective synthesis of (S)-and (R)-α-methylserines: application to the synthesis of (S)-and (R)-N-Boc-N, O-isopropylidene-α-methylserinals | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN113372271A (en) | Preparation method of cisatracurium besylate | |
| CN110922409A (en) | Method for preparing BTK inhibitor zebritinib | |
| CN112920053B (en) | Preparation method of chiral alpha-methyl aromatic ethylamine | |
| CN111362814B (en) | Synthetic method of rivastigmine chiral intermediate | |
| CN114380717A (en) | Process for the preparation of 3- (tert-butoxycarbonyl-methoxycarbonylmethyl-amino) -propionic acid methyl ester and intermediates thereof | |
| CN109574860B (en) | Method for preparing vilanterol | |
| CN113336761A (en) | Preparation method of JAK inhibitor key intermediate | |
| CN106866453B (en) | A kind of method that microreactor prepares scheme for lacosamide | |
| JP2003171335A (en) | Method for producing macrocyclic ketone compound | |
| CN112142629B (en) | Preparation method of 3-aminosulfonylalanine | |
| US6781016B2 (en) | Process for the preparation of alicyclic ketones and an alkyl-substituted alicyclic esters | |
| CN114195684B (en) | Synthesis method of amino protecting group N-substituted chiral amino acid | |
| WO2004075827A2 (en) | Process for the preparation of 2-[(diphenylmethyl) thio] acetamide | |
| CN103508999A (en) | Maxacalcitol synthesizing intermediate and preparation method and application thereof | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN113387874B (en) | Method for synthesizing 6, 6-dialkyl piperidine-2-carboxylic acid compound | |
| CN115286504B (en) | Method for synthesizing (R) -2- (2- (tert-butoxy) -2-oxyethyl) pentanoic acid | |
| CN115246784A (en) | Upatinib intermediate compound and preparation method thereof | |
| CN117486904A (en) | Synthesis and refining method of ganciclovir impurity | |
| CN111433189A (en) | Process for producing 11- β -hydroxysteroid dehydrogenase type 1 inhibitor | |
| CN117603128A (en) | Preparation method of (3R, 6S) -3-amino-6-methylpiperidine |
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 |