CN115124448A - Method for synthesizing D-pyroglutamic acid derivative by one-pot method - Google Patents
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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Abstract
The invention provides a method for synthesizing a D-pyroglutamic acid derivative by a one-pot method, which relates to the technical field of pharmaceutical chemical synthesis and comprises the following steps: the method comprises the steps of reacting D-pyroglutamic acid derivatives serving as raw materials with thionyl chloride and alcohol to obtain corresponding D-pyroglutamic acid ester, reacting the D-pyroglutamic acid ester with a protective group under the catalysis of DMAP to obtain a D-pyroglutamic acid derivative solution, and recrystallizing to obtain the pyroglutamic acid derivatives with the purity of over 98%. The invention provides a crystallization process of the D-pyroglutamic acid derivative, which simplifies the operation steps, has simple process conditions, cheap and easily obtained raw materials, short synthesis route and high product purity and yield, and lays a foundation for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for synthesizing a D-pyroglutamic acid derivative by a one-pot method.
Background
The structural formula of the D-pyroglutamic acid (Pyroglutamic acid) is shown as the following formula:
the chemical name of D-pyroglutamic acid is 2-pyrrolidone-5-carboxylic acid, which is formed by dehydrating alpha-amino and gamma-hydroxyl of glutamic acid to form intramolecular amido bond, or formed by losing amido group in glutamine molecule. D-pyroglutamic acid and derivatives thereof are widely applied to synthesis of drug intermediates, for example, patent CN109180683A discloses a synthesis method for preparing targeted anticancer drug ibrutinib by using D-pyroglutamic acid, patent CN108727243A discloses a preparation method for preparing 2-pyrrolidone by using D-pyroglutamic acid, and patent CN101128446B discloses a method for synthesizing intermediates of dextrocetirizine and levocetirizine by using pyroglutamate.
In the synthesis process of D-pyroglutamic acid and derivatives thereof, amino and carboxyl are protected, but the steric hindrance of amido bonds on the D-pyroglutamic acid and the derivatives thereof is large, a catalyst DMAP is required for catalytic reaction when protecting groups are formed, and meanwhile, alcohol and the protecting groups used in the esterification of the carboxyl can also react under the catalysis of DMAP to generate large impurities. At present, the pyroglutamic acid derivatives are prepared by adopting a two-step method in domestic and foreign industries, the intermediate D-pyroglutamic acid ester is separated and purified, and then the next step of amino protection is carried out, so that the process is complicated, and the overall yield is not high.
Patent CN101454309B discloses a method for synthesizing (2R) -N- (tert-butoxycarbonyl) pyroglutamic acid ethyl ester, wherein the intermediate product can be used in the next step without purification, but the product of the synthesis method needs to use preparative chromatography to purify D-pyroglutamic acid ethyl ester to obtain the final product (2R) -N- (tert-butoxycarbonyl) pyroglutamic acid ethyl ester, which is high in cost, only suitable for laboratory research work, and has no industrial premise and low industrial production feasibility.
At present, two-step method is usually adopted to synthesize pyroglutamic acid derivatives, the intermediate D-pyroglutamic acid ethyl ester needs column purification, the processing operation is complex, and the cost is high.
Therefore, based on the above disadvantages and defects, the present application aims to disclose a method for efficiently synthesizing D-pyroglutamic acid derivatives, so that the method has important industrial application value in the synthesis of D-pyroglutamic acid derivatives.
Disclosure of Invention
The invention provides a method for synthesizing D-pyroglutamic acid derivatives by a one-pot method aiming at the problems in the prior art, efficiently and conveniently protects amino and carboxyl of D-pyroglutamic acid, provides a crystallization process of the D-pyroglutamic acid derivatives, has no need of separation and purification of reaction intermediates, simplifies the synthesis steps, obtains better purity and yield, solves the problems of complex route and harsh reaction conditions in the preparation process, has simple process conditions and less three wastes, is suitable for industrial production, and has market competitiveness.
In order to realize the purpose, the technical scheme adopted by the invention is as follows:
a process for synthesizing D-pyroglutamic acid derivatives by a one-pot method has the general reaction route shown as the following formula:
the method mainly comprises the following steps:
(1) mixing the D-pyroglutamic acid derivative I with alcohol, adding thionyl chloride, and reacting to obtain a D-pyroglutamic acid ester derivative II, wherein the reaction formula is as follows:
(2) adding amino protecting group and catalyst into D-pyroglutamic acid ester derivative II solution to obtain oily matter, wherein the reaction formula is as follows:
(3) and (3) dropwise adding an anti-solvent into the oily substance obtained in the step (2), separating out a product, cooling, growing crystals, filtering and drying to obtain white to light yellow powder which is the D-pyroglutamic acid derivative III.
Wherein R of the D-pyroglutamic acid derivative I 1 The substituent is a group with higher steric hindrance on a nitrogen atom.
Preferably, R 1 Substituents include, but are not limited to, any of hydrogen, methyl, dimethyl, ethyl, propyl, isopropyl.
R of the D-pyroglutamate derivative II 2 The substituent is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
Preferably, R 2 The substituent is ethyl.
The reaction in the step (1) comprises the following specific processes: mixing and stirring the D-pyroglutamic acid derivative I and alcohol, and then dropwise adding thionyl chloride, controlling the temperature to be 0-50 ℃.
Preferably, the reaction in the step (1) comprises the following specific processes: mixing and stirring the D-pyroglutamic acid derivative I and alcohol, and then dropwise adding thionyl chloride, controlling the temperature to be 10-30 ℃.
The treatment process of the product D-pyroglutamic acid ester derivative II in the step (1) comprises the following steps: after the excess thionyl chloride is neutralized with an alkaline solution, it is concentrated under reduced pressure and the corresponding alcohol is evaporated to dryness.
The reaction in the step (2) comprises the following specific processes: adding a catalyst and DCM into the solution of the D-pyroglutamate derivative II, dropwise adding an amino protecting group at 10-25 ℃, and keeping the temperature; after the reaction was finished, the mixture was washed once with water, separated, and the DCM layer was concentrated under reduced pressure at controlled temperature until DCM residue was obtained.
The catalyst in the step (2) is DMAP, and the molar ratio of the DMAP is 0.005eq-0.1 eq.
Further preferably, the molar ratio of the catalyst DMAP in step (2) is 0.05 eq.
The amino protecting group in the step (2) includes but is not limited to any one of Boc, Cbz, Fmoc and Alloc.
The reaction in the step (3) comprises the following specific processes: and (3) dropwise adding an anti-solvent into the oily substance obtained in the step (2), gradually separating out a product, cooling to 0-10 ℃, growing crystals for 1h, filtering, and drying to obtain white to light yellow powder which is D-pyroglutamic acid derivative III.
Preferably, the antisolvent in the step (3) is n-heptane, n-hexane or cyclohexane.
Further preferably, the antisolvent in the step (3) is n-heptane.
Preferably, the mass ratio of the dosage of the anti-solvent added dropwise in the step (3) to the D-pyroglutamic acid derivative I is 2-5: 1.
In the present invention, the term "Boc" is a short term for the group "t-butyloxycarbonyl", which has the formula
In the present invention, the term "Cbz" is a abbreviation for the group "benzyloxycarbonyl" having the formula
In the present invention, the term "Fmoc" is a group of 9-fluorenylmethyloxycarbonyl for short, and the structural formula thereof is
In the present invention, the term "Alloc" is a abbreviation for the group "allyloxycarbonyl", which has the formula
In the present invention, the term "DMAP" is abbreviated as "4-dimethylaminopyridine", having the formula
In the present invention, the term "DCM" is an abbreviation for the group "dichloromethane", having the formula
Compared with the prior art, the invention has the following beneficial effects:
1. the method for synthesizing the D-pyroglutamic acid derivative has the advantages that the purity of the obtained product is more than 98 percent, the yield of two steps is more than 90 percent, and the yield is improved by 20 percent compared with the traditional process.
2. Compared with the traditional two-step synthesis method, the synthesis method of the D-pyroglutamic acid derivative does not need to separate and purify the intermediate, simplifies the synthesis process, reduces production equipment, shortens production time, and is suitable for industrial production.
3. The invention adopts a crystallization method to remove impurities generated by the reaction, and realizes the synthesis of the high-purity D-pyroglutamic acid derivative with high efficiency.
Drawings
FIG. 1 is an HPLC chromatogram of Boc-D-pyroglutamic acid ethyl ester in example 1 of the present invention.
FIG. 2 is an LC-MS spectrum of Boc-D-pyroglutamic acid ethyl ester in example 1 of the present invention.
FIG. 3 is an HPLC chromatogram of Boc-D-pyroglutamic acid methyl ester in example 2 of the present invention.
Detailed Description
The following non-limiting examples will provide those of ordinary skill in the art with a more complete understanding of the present invention, but are not intended to limit the invention in any way. The following is merely an exemplary illustration of the scope of the claims of the present application and various changes and modifications of the invention of the present application may be made by those skilled in the art based on the disclosure, which should also fall within the scope of the claims of the present application.
The present invention will be further described below by way of specific examples. The various chemicals used in the examples of the present invention were obtained by conventional commercial routes unless otherwise specified. The contents are all mass contents hereinafter.
In the examples described below, the D-pyroglutamic acid was purchased from Hadamard Beta (Shanghai) Chemicals, Inc. (Lot. C01297769); the ethanol is purchased from Hangzhou Tian dynasty chemicals Co., Ltd (batch number: QC 20220504); the thionyl chloride was purchased from Shanghai Tatankojiki GmbH (batch No. P2106196); the sodium bicarbonate was purchased from Shanghai Tantake Technique, Inc. (batch No.: P1795903); the DMAP was purchased from Shanghai Tantake Technique, Inc. (batch No.: P1389431); the DCM was purchased from Hangzhou Tian dynasty chemicals, Inc. (batch No. 20220404); the di-tert-butyl dicarbonate is purchased from Ningxia jinxiang pharmaceutical chemical Co., Ltd. (batch No. 202108016); the citric acid was purchased from Shanghai Michelin Biochemical technology Ltd (batch No. C12227925); the n-heptane was purchased from Hangzhou Tian dynasty chemicals, Inc. (batch No. 20211205); the methanol was purchased from Hangzhou Tian dynasty chemicals, Inc. (batch No. 20220311); the sodium carbonate was purchased from Shanghai Tantake Technique, Inc. (batch No.: P1678912).
Purity (HPLC) determination method: an Agilent1260 chromatograph is selected and provided with an ultraviolet detector; the type of the chromatographic column: agilent Eclipse XDB-C18150X 4.6mm, 3.5 um; column temperature: 40 ℃; detection wavelength: 210 nm; sample introduction amount: 5 microliter; mobile phase: mobile phase A: 0.1% phosphoric acid solution, mobile phase B: and (3) acetonitrile.
EXAMPLE 1 preparation of Boc-D-pyroglutamic acid ethyl ester
Adding 50g of D-pyroglutamic acid I and 50g of ethanol into a reaction bottle, stirring, cooling to 0 ℃, controlling the temperature to be 0-30 ℃, and dropwise adding 48.4g of thionyl chloride until the dripping is finished. Reacting at 20-30 ℃ for 2h, dropwise adding 330g of saturated sodium bicarbonate solution into the reaction solution after the reaction is finished, adjusting the pH of the system to 7, concentrating under reduced pressure, evaporating ethanol to obtain D-pyroglutamic acid ethyl ester II, adding 2.33g of DMAP and 150g of DCM into the reaction system, dropwise adding di-tert-butyl dicarbonate at the temperature of 10-25 ℃, and completing the dropwise adding. Reacting at 10-25 ℃ for 1h, separating liquid after the reaction is finished, washing an organic phase once by using 10% citric acid water, concentrating the organic phase to an oily substance, dropwise adding 150g of n-heptane to the oily substance to separate out white crystals, growing the crystals at 0-10 ℃ for 1h, filtering and drying to obtain 90.7g of white solid Boc-D-pyroglutamic acid ethyl ester III (theoretical yield: 99.7g) with the yield of 91.0%, and performing HPLC: 98.9 percent.
EXAMPLE 2 preparation of Boc-D-pyroglutamic acid methyl ester
50g D-pyroglutamic acid I and 50g of methanol are added into a reaction bottle and stirred, the temperature is reduced to 0 ℃, 48.4g of thionyl chloride is dripped at the temperature of 0-30 ℃, and the dripping is finished. Reacting for 2h at 20-30 ℃. After the reaction, 200g of saturated sodium carbonate solution is dropwise added into the reaction solution, the pH value of the system is adjusted to be 8, the mixture is concentrated under reduced pressure, methanol is evaporated to dryness to obtain D-pyroglutamic acid methyl ester II, 2.33g of DMAP and 150g of DCM are added into the reaction system, the temperature is controlled to be 10-25 ℃, and di-tert-butyl dicarbonate is dropwise added, and the dropwise addition is completed. Reacting at 10-25 ℃ for 1h, separating liquid after the reaction is finished, washing an organic phase once by using 10% citric acid water, concentrating the organic phase to an oily substance, dropwise adding 200g of n-heptane to the oily substance to separate out white crystals, growing the crystals at 0-10 ℃ for 1h, filtering and drying to obtain 86.7g of white solid Boc-D-pyroglutamic acid methyl ester III (theoretical yield: 94.2g) with the yield of 92.0%, and performing HPLC: 99.0 percent.
Comparative example 1 preparation of Boc-D-Pyroglutamic acid Ethyl ester
Adding 10g of D-pyroglutamic acid I and 10g of ethanol into a reaction bottle, stirring, cooling to 0 ℃, controlling the temperature to be 0-30 ℃, and dropwise adding 9.7g of thionyl chloride after dropwise adding. Reacting for 2h at 20-30 ℃, dropwise adding 66g of saturated sodium bicarbonate solution into the reaction solution after the reaction is finished, adjusting the pH of the system to be 7, concentrating under reduced pressure, evaporating ethanol to obtain D-pyroglutamic acid ethyl ester II, adding 0.47g of DMAP and 30g of DCM into the reaction system, controlling the temperature to be 10-25 ℃, and dropwise adding di-tert-butyl dicarbonate until the dropwise adding is finished. Reacting at 10-25 ℃ for 1h, separating liquid after the reaction is finished, washing the organic phase once by using 10% citric acid water, concentrating the organic phase to oily matter, adding 50g of drinking water into the oily matter, reducing the temperature to 0 ℃, stirring and solidifying to obtain white crystals, filtering and drying to obtain 18.1g of white solid ethyl Boc-D-pyroglutamate III (the theoretical yield is 19.9g), the yield is 91.0%, and HPLC: 93.8 percent.
Compared with the example 1, the comparative example 1 selects drinking water as the anti-solvent for crystallization treatment during product purification, and the product purity only reaches 93.8 percent, which is obviously reduced.
Comparative example 2 preparation of Boc-D-Pyroglutamic acid Ethyl ester
Adding 10g of D-pyroglutamic acid I and 10g of ethanol into a reaction bottle, stirring, cooling to 0 ℃, controlling the temperature to be 0-30 ℃, and dropwise adding 9.7g of thionyl chloride after dropwise adding. Reacting at 20-30 ℃ for 2h, dropwise adding 66g of saturated sodium bicarbonate solution into the reaction solution after the reaction is finished, adjusting the pH of the system to be 7, concentrating under reduced pressure, distilling out part of ethanol, cooling to 0-5 ℃, stirring for crystallization for 2 hours, filtering and drying to obtain 9.7g of D-pyroglutamic acid ethyl ester II (theoretical yield: 12.2g), and the yield is 79.7%.
10g of D-pyroglutamic acid ethyl ester II, 0.40g of DMAP and 30g of DCM are added with di-tert-butyl dicarbonate dropwise at the temperature of 10-25 ℃ after the dropwise addition is finished. Reacting at 10-25 ℃ for 1h, separating liquid after the reaction is finished, washing an organic phase once by using 10% citric acid water, concentrating the organic phase to an oily substance, dropwise adding 30g of n-heptane to the oily substance to separate out white crystals, growing the crystals at 0-10 ℃ for 1h, filtering and drying to obtain 15.8g of white solid Boc-D-pyroglutamic acid ethyl ester III (theoretical yield: 16.4g) with the yield of 96.5%, and performing HPLC: 98.6 percent. The overall yield of the two steps was 76.9%.
Compared with the example 1, the Boc-D-pyroglutamic acid ethyl ester is synthesized by adopting a two-step method in the comparative example 2, the total yield is obviously reduced, the process is more complex, the operation is more, and the product quality is not obviously improved.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A method for synthesizing D-pyroglutamic acid derivatives by a one-pot method is characterized by comprising the following steps:
(1) mixing the D-pyroglutamic acid derivative I with alcohol, adding thionyl chloride, and reacting to obtain a D-pyroglutamic acid ester derivative II, wherein the reaction formula is as follows:
(2) adding amino protecting group and catalyst into D-pyroglutamic acid ester derivative II solution to obtain oily matter, wherein the reaction formula is as follows:
(3) and (3) dropwise adding an anti-solvent into the oily substance obtained in the step (2), separating out a product, cooling, growing crystals, filtering and drying to obtain white to light yellow powder which is the D-pyroglutamic acid derivative III.
2. The method of claim 1, wherein: r of the D-pyroglutamic acid derivative I 1 The substituent is selected from a group with higher steric hindrance on a nitrogen atom, and R is 1 The substituent is any one of hydrogen, methyl, dimethyl, ethyl, propyl or isopropyl.
3. The method of claim 1, wherein: r of the D-pyroglutamate derivative II 2 The substituent is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
4. The method of claim 1, wherein: the treatment process of the product D-pyroglutamic acid ester derivative II in the step (1) comprises the following steps: excess thionyl chloride is neutralized with an aqueous solution of an inorganic base and the alcohol is evaporated to dryness.
5. The method of claim 1, wherein: the catalyst in the step (2) is DMAP, and the molar ratio of the DMAP is 0.005eq-0.1 eq.
6. The method of claim 5, wherein: the molar ratio of DMAP was 0.05 eq.
7. The method of claim 1, wherein: the amino protecting group in the step (2) is any one of Boc, Cbz, Fmoc or Alloc.
8. The method of claim 1, wherein: the anti-solvent in the step (3) is any one or more of n-heptane, n-hexane or cyclohexane.
9. The method of claim 8, wherein: the anti-solvent is n-heptane.
10. The method of claim 1, wherein: the mass ratio of the anti-solvent dosage in the step (3) to the D-pyroglutamic acid derivative I is 2-5: 1.
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| CN103435535A (en) * | 2013-09-09 | 2013-12-11 | 嘉兴学院 | Preparation method of R-proline having cyclopropane structure |
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| CN109721522A (en) * | 2018-12-29 | 2019-05-07 | 常州吉恩药业有限公司 | A kind of high-quality N- tertbutyloxycarbonyl-L-Glutimic acid benzyl ester industrialized preparing process |
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