CN113061096A - Preparation method of stable isotope labeled krusel - Google Patents

Preparation method of stable isotope labeled krusel Download PDF

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CN113061096A
CN113061096A CN202110335683.6A CN202110335683A CN113061096A CN 113061096 A CN113061096 A CN 113061096A CN 202110335683 A CN202110335683 A CN 202110335683A CN 113061096 A CN113061096 A CN 113061096A
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solvent
stable isotope
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张磊
曹炜东
韩世磊
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Tianjin Alta Scientific Co ltd
Alta Tianjin Certified Reference Materials Research Institute Co ltd
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    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

The invention relates to a preparation method of stable isotope labeled kremen, which comprises the steps of taking 3, 5-dichloro-4-aminoacetophenone (II) as a raw material, preparing a compound (III) through bromination reaction, performing improved drape Rael (Gabriel) synthesis reaction, performing amination reaction with dimethylamido disodium to obtain a compound (IV), hydrolyzing and reducing to obtain a compound (VI), and performing reductive amination reaction to obtain a target compound (I). The preparation method has reasonable process design, low raw material price, controllable experimental process, simple and convenient operation, and can conveniently synthesize various required labeled compounds, such as D label,13C flag or D-13The target product prepared from the C double-labeled compound has high purity, can be used as an internal standard substance in the field of food safety detection, and has important practical application value.

Description

Preparation method of stable isotope labeled krusel
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of stable isotope labeled krusel.
Background
Klenopro belongs to a beta2Receptor agonists, in addition to their use in the treatment of bronchitis and asthmatic bronchitis, are also used as feed additives to increase the rate of lean tissue, the residues of which accumulate in animals, the 2011 national institutes of food safety committee office "clenbuterol" special treatment protocol [ food safety agency (2011) No. 14 ] specifically lists kruselonela and prohibits its use in animal feed. At present, the pretreatment of the detection method for the krusel-lonone residue in food in China is complicated, and the influence of the pretreatment of matrix effect and the like on the measurement result is large. The developed countries generally adopt isotope dilution mass spectrometry, errors in the method can be effectively corrected, and the stability of the detection method is obviously improved.
Isotope Dilution Mass Spectrometry (IDMS) adopts a stable Isotope labeled compound as an internal standard reagent, well combines the separation capacity of chromatography and the qualitative capacity of Mass Spectrometry, is determined as the most authoritative arbitration detection method for food safety detection internationally, and is listed as a relevant test standard by developed countries of the United states, European Union, Japan and the like. The Isotope Dilution Mass Spectrometry (IDMS) adopts a stable Isotope labeling compound as an internal standard reagent, well combines the separation capability of chromatography and the qualitative capability of Mass Spectrometry, can achieve the aim of accurate quantification by detecting the ratio of ions with corresponding Mass numbers and comparing the ratio with the standard ratio, simultaneously effectively eliminates the matrix effect and the recovery rate difference caused in the pretreatment process of a sample, and improves the detection accuracy, and the IDMS is the only measurement method which can be used for the authoritativeness of trace, trace and ultra-trace elements. Meanwhile, when the stable isotope labeling reagent is used as an internal standard reagent in isotope dilution mass spectrometry, at least 3 mass number differences are generally required. In China, the isotope labeled Kronchoc used by the method completely depends on imported products, and the factors such as price, shelf life and the like seriously restrict the application of the IDMS technology in the relevant detection field of China.
The method has important significance for efficiently preparing the stable isotope labeled kruselonone meeting the requirement of an internal standard reagent at low cost. At present, a synthetic method of stable isotope labeled kremen-pro is reported in Chinese patent CN 105968021A, but the method has the problems of expensive isotope labeled raw materials, difficult separation and purification of intermediates in the synthetic process, more byproducts in the amination process, long synthetic steps, low overall yield, high synthetic cost, unsuitability for large-scale preparation and the like, and cannot fundamentally solve the current situation that the detection field in China depends on imported products.
Based on the situation, the invention creatively designs a more reasonable preparation route, prepares the stable isotope labeled kruseloney by using the simple and easily obtained raw materials of 3, 5-dichloro-4-aminoacetophenone and isotope labeled acetone as raw materials, has short synthesis route, has the total yield of 27.6 percent calculated by the 3, 5-dichloro-4-aminoacetophenone, obtains products with higher chemical purity and isotope abundance, can be used as an internal standard substance in the field of food quality inspection, and has important practical application value.
Disclosure of Invention
In view of the above, the present invention aims to overcome the defects in the prior art, and provides a method for preparing isotope-labeled krusel-propiolactone with high efficiency and stability, wherein 3, 5-dichloro-4-aminoacetophenone is used as a starting material, and a target product is obtained through five steps of conventional chemical reactions.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a preparation method of stable isotope labeled kremen-propile comprises the following steps:
(1) reacting the compound II in a solvent by using a brominating reagent to obtain an intermediate III;
(2) reacting the intermediate III in a solvent by using an amination reagent, namely dimethyl amido sodium to obtain an intermediate IV;
(3) hydrolyzing the intermediate IV under an acidic condition to obtain an intermediate V;
(4) the intermediate V is reacted in a solvent through a reducing agent to obtain an intermediate VI;
(5) the intermediate VI and stable isotope labeled acetone are subjected to reductive amination reaction in a solvent to obtain a target compound I;
the reaction route is as follows:
Figure BDA0002997742160000021
further, in the step (1), the solvent is chloroform, ethyl acetate, tetrahydrofuran, methanol, acetonitrile or a mixed solvent of the above solvents, preferably a mixed solvent of ethyl acetate and chloroform;
in the step (1), the brominating reagent is copper bromide, bromine or NBS, preferably copper bromide;
the molar ratio of the compound II to the brominating agent is (1: 1) to (1: 12), preferably (1: 2).
Further, the reaction temperature in the step (1) is 25-100 ℃, and preferably 80 ℃;
the reaction time in the step (1) is 1-48 h, and preferably 16 h.
Further, in the step (2), the solvent is dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, preferably acetonitrile;
the molar ratio of the compound (III) to the amination reagent is (1: 1) to (1: 5).
Further, in the step (2), the reaction temperature is 10-100 ℃, and the reaction time is 1-48 h.
Further, in the step (3), the acidic condition is hydrochloric acid or sulfuric acid reagent or organic solution of the acidic reagent;
preferably, the acidic reagent in step (3) is an aqueous hydrochloric acid solution or an organic hydrochloric acid solution, and more preferably, an aqueous hydrochloric acid solution, and the concentration of the acidic reagent is 5% to 37%.
Further, the solvent in the step (4) is methanol, ethanol, tetrahydrofuran or a mixed solvent thereof, and more preferably, the solvent is methanol;
the reducing agent is sodium borohydride, potassium borohydride, diborane or hydrogen, preferably potassium borohydride;
more preferably, the molar ratio of the compound (V) to the reducing agent in the step (4) is (1: 1) to (1: 3), and more preferably, the molar ratio is (1: 3).
Further, the solvent in the step (5) is deuterated methanol, deuterated ethanol, tetrahydrofuran or a mixed solvent of the above, preferably deuterated methanol;
the deuterated methanol in the step (5) is CH3OD or CD3OD, more preferably, the solvent is CH3OD。
Further, the stable isotope labeled acetone in the step (5) may be acetone-D6Acetone-13C3Or acetone-2-13C；
The reducing agent in the step (5) is sodium borohydride, potassium borohydride, lithium aluminum hydride, deuterated sodium borohydride, deuterated lithium aluminum hydride, deuterated potassium borohydride, hydrogen or deuterium gas, preferably sodium boron deuteride or sodium borohydride;
in the step (5), the molar ratio of the compound VI to the reducing agent is (1: 1) to (1: 3), and more preferably, the molar ratio is 1: 1.5.
compared with the prior art, the invention has the beneficial effects that:
the preparation method of the stable isotope labeled kremen-propile has short steps and undiluted isotope abundance. The route of the invention does not need to use expensive isotope labeled isopropylamine as a labeling reagent, and the used stable isotope labeling reagent D labels acetone or13The price of the C-marked acetone is low. And the key isotope compound synthesis step is arranged in the last step in the reaction step, so that the operability and atom economy of the process are greatly improved, more importantly, the isotope-labeled isopropylamine is synthesized without at least 5 steps of reaction, the synthesis cost of the labeled compound is greatly reduced, the repeatability and the stability are higher, and various required labeled compounds, such as D-labeled compounds, D-labeled compounds and the like, can be conveniently synthesized,13C flag or D-13C double-labeled compound. The preparation route and the preparation method are not reported in documents, and the obtained stable isotope labeled kruselonone has the chemical purity of more than 99 percentThe abundance of the site elements is more than 98 percent, the total yield can reach 27.6 percent by the 3, 5-dichloro-4-aminoacetophenone, and the stable isotope labeled kronecker obtained by the preparation method can be used as an internal standard substance in the field of food quality inspection and has important practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is an ESI-MS spectrum of Clevelopromide-D7 obtained in example 5;
FIG. 2 shows the preparation of Clontroprione-D7 from example 51HNMR spectrogram.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to examples below:
example 1: preparation of Compound (III):
Figure BDA0002997742160000041
in a 1L three-necked flask, 3, 5-dichloro-4-aminoacetophenone (compound II) (30g, 0.147mol) and ethyl acetate (200mL), chloroform (150mL), copper bromide (65.5g, 0.294mol) were added, warmed to 80 ℃ and stirred for 16 h. After the reaction, the reaction solution was filtered while it was hot, the filtrate was concentrated, 300mL of methylene chloride and 200mL of water were added to extract the mixture, the methylene chloride phase was concentrated to about 150mL, a large amount of solid was precipitated, and 28g of the compound (III) was obtained by filtration in a yield of 67%.
Comparative example 1: preparation of Compound (III):
3, 5-dichloro-4-aminoacetophenone (5g, 0.025mol) and chloroform (30mL) were added to a reaction flask, and a solution of bromine (4.8g,1.2e q) in chloroform (30mL) was added dropwise under ice-bath. After the addition, the temperature is returned to the room temperature, and the reaction is continued for about 2 hours. After the reaction, the reaction solution was washed with an aqueous solution of sodium bicarbonate, dried, filtered, the filtrate was concentrated, and the crude product was purified by Flash column chromatography to obtain 4.2g of compound (III) with a yield of 60%.
Example 2: preparation of Compound (IV):
Figure BDA0002997742160000051
in a 1L round-bottom flask, compound (III) (27g, 0.095mol), sodium dicarboxamide (IV) (11g, 0.11mol), acetonitrile (400mL) were added, and the mixture was raised to 70 ℃ and stirred for 2 h. After the reaction, water was added to the system to quench the reaction, extraction was performed with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was slurried with MTBE to give 23g of Compound (IV) in 88.1% yield.
Example 3: preparation of Compound (V):
Figure BDA0002997742160000052
in a 1L round bottom flask, compound (IV) (23g, 0.084mol), 6N HCl (100mL) was added, raised to 80 ℃ and stirred for 1 h. After completion of the reaction, the reaction mixture was cooled to precipitate a solid, which was then filtered to obtain 21g of compound (V) in 85.7% yield.
Example 4: preparation of Compound (VI):
Figure BDA0002997742160000053
in a 1L round bottom flask, compound (V) (21g, 0.072mol), methanol (250mL) was added and potassium borohydride (10g, 0.185mol) was added slowly and stirred at room temperature for 1 h. After the reaction, water and dichloromethane were added for extraction, concentration was carried out, and the crude product was purified by Flash column chromatography to obtain 15g of compound (VI) with a yield of 94.9%.
Comparative example 2: clontracene Proro-D7System of (1)Preparing:
compound (V) (5g, 0.023mol), acetone-D6(2.9g, 0.045mol) was dissolved in methanol-D (30mL), and sodium cyanoborodeuteride (2.2g, 0.034mol) and a catalytic amount of acetic acid were added in portions and the reaction was stirred at room temperature for 2 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution and dichloromethane for extraction, concentrating the dichloromethane, and purifying the crude product by Flash column chromatography to obtain 3.2g of the compound (I), wherein the yield is 52.7 percent, and the isotopic abundance is 98.1 percent through MS detection.
Example 5: target Compound I Clontroprione-D7The preparation of (1):
Figure BDA0002997742160000061
in a 1L round-bottom flask, Compound (V) (5g, 0.023mol), methanol-D (30mL), acetone-D were added6(2.9g, 0.045mol), stirred at room temperature for 2h, slowly added with sodium borodeuteride (1.4g, 0.033mol), and stirred at room temperature for 14 h. After the reaction is finished, water and dichloromethane are added for extraction, dichloromethane is concentrated, the crude product is purified by Flash column chromatography to obtain 3.5g of the compound (I), the yield is 57.4%, and the isotopic abundance is 98.3% by MS detection.
Experimental example 1:
detected by ESI-MS, the kruselarpur-D7Molecular ion peak of [ M + H ]]+270.2, and the theoretical calculation result [ M + H [ ]]+270.1, with an isotopic abundance of 98.3%; the nuclear magnetic resonance analysis shows that the structure of the compound accords with the target structure, the structure is correct, and the data are analyzed:1H NMR(400MHz,MeOD)δ7.21(s,2H),4.58(dd,J＝8.9,4.1Hz,1H),2.69(qd,J＝12.0,6.5Hz,2H)。
the above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (9)

1. A preparation method of stable isotope labeled kremen-propile is characterized in that: the method comprises the following steps:
(1) reacting the compound II in a solvent by using a brominating reagent to obtain an intermediate III;
(2) reacting the intermediate III in a solvent by using an amination reagent, namely dimethyl amido sodium to obtain an intermediate IV;
(3) hydrolyzing the intermediate IV under an acidic condition to obtain an intermediate V;
(4) the intermediate V is reacted in a solvent through a reducing agent to obtain an intermediate VI;
(5) the intermediate VI and stable isotope labeled acetone are subjected to reductive amination reaction in a solvent to obtain a target compound I;
the reaction route is as follows:
Figure FDA0002997742150000011
2. the method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
in the step (1), the solvent is chloroform, ethyl acetate, tetrahydrofuran, methanol, acetonitrile or a mixed solvent of the above solvents, preferably a mixed solvent of ethyl acetate and chloroform;
in the step (1), the brominating reagent is copper bromide, bromine or NBS, preferably copper bromide;
the molar ratio of the compound II to the brominating agent is (1: 1) to (1: 12), preferably (1: 2).
3. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
the reaction temperature in the step (1) is 25-100 ℃, and preferably 80 ℃;
the reaction time in the step (1) is 1-48 h, and preferably 16 h.
4. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
in the step (2), the solvent is dichloromethane, trichloromethane, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone, preferably acetonitrile;
the molar ratio of the compound (III) to the amination reagent is (1: 1) to (1: 5).
5. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
in the step (2), the reaction temperature is 10-100 ℃, and the reaction time is 1-48 h.
6. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
in the step (3), the acidic condition is hydrochloric acid or sulfuric acid reagent or organic solution of the acidic reagent;
preferably, the acidic reagent in step (3) is an aqueous hydrochloric acid solution or an organic hydrochloric acid solution, and more preferably, an aqueous hydrochloric acid solution, and the concentration of the acidic reagent is 5% to 37%.
7. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
the solvent in the step (4) is methanol, ethanol, tetrahydrofuran or a mixed solvent of the above, and more preferably, the solvent is methanol;
the reducing agent is sodium borohydride, potassium borohydride, diborane or hydrogen, preferably potassium borohydride;
more preferably, the molar ratio of the compound (V) to the reducing agent in the step (4) is (1: 1) to (1: 3), and more preferably, the molar ratio is (1: 3).
8. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
the solvent in the step (5) is deuterated methanol, deuterated ethanol, tetrahydrofuran or a mixed solvent of the deuterated methanol and the deuterated ethanol, preferably deuterated methanol;
the deuterated methanol in the step (5) is CH3OD or CD3OD, more preferably, the solvent is CH3OD。
9. The method of claim 1, wherein the stable isotope labeled kronexol is prepared by the following steps:
the stable isotope labeled acetone in the step (5) can be acetone-D6Acetone-13C3Or acetone-2-13C；
The reducing agent in the step (5) is sodium borohydride, potassium borohydride, lithium aluminum hydride, deuterated sodium borohydride, deuterated lithium aluminum hydride, deuterated potassium borohydride, hydrogen or deuterium gas, preferably sodium boron deuteride or sodium borohydride;
in the step (5), the molar ratio of the compound VI to the reducing agent is (1: 1) to (1: 3), and more preferably, the molar ratio is 1: 1.5.
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Application publication date: 20210702