CN113149851A - Preparation method of stable isotope labeled chlorpropaline - Google Patents

Preparation method of stable isotope labeled chlorpropaline Download PDF

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CN113149851A
CN113149851A CN202110333425.4A CN202110333425A CN113149851A CN 113149851 A CN113149851 A CN 113149851A CN 202110333425 A CN202110333425 A CN 202110333425A CN 113149851 A CN113149851 A CN 113149851A
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chlorpropaline
stable isotope
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张磊
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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    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract

The invention relates to a preparation method of stable isotope labeled chloropropaneline, which takes 2-bromo-2' -chloroacetophenone as a starting material and is synthesized by improved Gabriel (Gabriel) of cover cloth (the starting material and an amination reagent sodium diformylamide are subjected to nucleophilic substitutionReaction), hydrolysis, reduction and reductive amination are carried out for four steps in total to synthesize the isotope labeled chlorpropaline. The preparation method of the invention adopts four-step conventional chemical reaction, 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 purity of a target product prepared from the C double-labeled compound is high and reaches more than 98%, the total yield is more than 66%, the isotopic abundance of a final product can reach more than 98%, the isotopic abundance dilution phenomenon is avoided, the reproducibility and the stability are higher, and the obtained target compound can provide a standard reagent for accurately determining the trace residue of the chlorpropalin.

Description

Preparation method of stable isotope labeled chlorpropaline
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of stable isotope labeled chlorpropaline.
Background
Chlorpropaline is a novel beta 2 receptor agonist that, in addition to its use in the treatment of bronchitis and asthmatic bronchitis, is also used as a feed supplement to increase the rate of lean tissue, the residue of which accumulates in animals. At present, for the content detection of chlorpropaline, a traditional liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry combined method and other rapid detection methods are mainly adopted. The traditional liquid phase and gas chromatography-mass spectrometry combined method is greatly influenced by matrix effect, particularly, samples for detecting chlorphenamine are mostly meat, urine and the like, the sample matrixes are complex in composition and difficult to process, and in addition, the detection result is easy to generate large deviation by an unscientific pretreatment method, so that the limitation of using the traditional detection method is large. 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 comparing the ratio of ions with corresponding Mass numbers to the ratio of standards, and simultaneously effectively eliminates matrix effect and recovery rate difference caused in the pretreatment process of samples, thereby improving the detection accuracy. Therefore, the method is an analysis method with high accuracy and precision. Stable isotope labeling reagents used as internal standard reagents in isotope dilution mass spectrometry generally require at least 3 mass number differences. In China, the isotope labeled chlorpropaline used by the method completely depends on imported products, and the application of the IDMS technology in relevant detection fields of China is severely restricted by factors such as price, shelf life and the like.
Figure RE-GDA0003090297040000011
The synthesis of chlorpropaline with natural abundance and stable isotope labeling is reported at home and abroad. In the literature (KOSHINAKA, Yakugaku Zasshi Journal of the Pharmaceutical Society of Japan,1978), α -formyl o-chloroacetophenone is used as a raw material, and the raw material is aminated with isopropylamine and then reduced to obtain chlorphenamine, but the separation and purification of chlorphenamine are difficult and the yield is low. In chinese patent (CN108911995A), synthesis of stable isotope labeled chloropropaline is reported, and in literature (feifa blanco, fine chemical engineering, 2020), deuterated acetone is used as a raw material, deuterated isopropylamine is synthesized through a 5-step reaction, and chloropropaline-D6 at different labeled sites is synthesized through a 3-step chemical reaction. The synthesis methods all relate to the problems that an intermediate in the synthesis process is difficult to separate and purify, byproducts are more in the amination process, the synthesis steps are long, the overall yield is low, the synthesis cost is high, the method is not suitable for large-scale preparation and the like, and the current situation that the detection field of China depends on imported products cannot be fundamentally solved.
The invention designs a synthetic route with high yield, simple and convenient operation and high isotope abundance, takes cheap 2-bromo-2' -chloroacetophenone and isotope labeled acetone as raw materials, has short synthetic route, high total yield which is more than 66 percent and low cost, and can provide a standard reagent for accurately determining the trace residue of the chlorpropalin.
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 chlorpropaline with high efficiency and stability, wherein 2-bromo-2' -chloroacetophenone is used as a starting material, and is subjected to nucleophilic substitution reaction with an amination reagent sodium diformylamide, hydrolysis, reduction, and reductive amination with isotope-labeled acetone to synthesize stable isotope-labeled chlorpropaline.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a preparation method of stable isotope labeled chlorpropaline comprises the following steps:
(1) taking a compound I as a raw material, and carrying out nucleophilic substitution reaction with an amination reagent sodium diformylamide in an organic solvent to generate an intermediate compound II;
(2) synthesizing an intermediate compound III by a hydrolysis reaction of the intermediate compound II under an acidic condition;
(3) reacting the intermediate compound III in a solvent under the action of a reducing agent to obtain an intermediate IV;
(4) reacting the intermediate compound IV with stable isotope labeled acetone in a solvent under the action of a reducing agent to obtain a target compound V;
the reaction route is as follows:
Figure RE-GDA0003090297040000021
further, the organic solvent in step (1) is tetrahydrofuran, acetonitrile or acetone, and more preferably, the organic solvent is acetonitrile.
In the step (1), the molar ratio of the compound I to the amination reagent is (1: 1) to (1: 5).
Further, the acidic condition in the step (2) is hydrochloric acid, a sulfuric acid reagent or an aqueous solution or an organic solution of the acidic reagent;
preferably, the acidic reagent in step (2) 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 (3) is methanol, ethanol, tetrahydrofuran or a mixed solvent thereof, and more preferably, the solvent is methanol;
the reducing agent in the step (3) is sodium borohydride, potassium borohydride, diborane or hydrogen, preferably sodium borohydride.
Further, the molar ratio of the compound III to the reducing agent in the step (3) is (1: 1) to (1: 3), and more preferably, the molar ratio is (1: 3).
Further, the solvent in the step (4) is deuterated methanol, deuterated ethanol, tetrahydrofuran or a mixed solvent of the above, preferably deuterated methanol;
more preferably, the deuterated methanol in the step (4) is CH3OD or CD3OD, more preferably, the solvent is CH3OD。
Further, the isotope-labeled acetone in the step (4) is acetone-D6Acetone-13C3Or acetone-2-13C；
The reducing agent in the step (4) is sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium deuteroborohydride, lithium aluminum hydride, potassium deuteroborohydride, hydrogen or deuterium; sodium deuteride or sodium borohydride is preferred.
Further, in the step (4), the molar ratio of the compound III 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 chloropropaneline obtains a target product through conventional chemical reaction and four-step reaction, has reasonable process design, low raw material price, cost saving, controllable experimental process and simple and convenient operation, ensures that the purity of the prepared target product is high and reaches more than 98 percent, the total yield reaches more than 66.0 percent, and places the key isotope compound synthesis step in the reaction step at the last step, greatly improves the operability and the atom economy of the process, more importantly, synthesizes isotope labeled isopropylamine without at least 5 steps of reaction, greatly reduces the synthesis cost of the labeled compound, has higher reproducibility and stability, and can conveniently synthesize various required labeled compounds, such as D-labeled compounds,13C flag or D-13The isotope abundance of the final product can be monitored by the C double-labeled compound, and the C double-labeled compound has more than 98 percent and no isotope abundanceThe stable isotope labeled chlorpropaline compound prepared by the invention can provide a standard sample for the food detection industry.
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 a schematic representation of chlorpropaline-D7 from example 41HNMR spectrogram;
FIG. 2 shows the preparation of chlorpropaline from control 11HNMR spectrogram;
FIG. 3 shows the preparation of chloropropaneline-D7 from example 413CNMR spectrogram;
FIG. 4 is a graph showing that chlorpropaline is obtained in comparative example 113CNMR spectrogram;
FIG. 5 is an ESI-MS spectrum of chloropropaneline-D7 obtained in example 4.
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: synthesis of intermediate II
Figure RE-GDA0003090297040000041
The starting material 2-bromo-2' -chloroacetophenone (compound I) (10.0g) was dissolved in 100mL of acetonitrile, sodium diformylamide (1.2eq,7.0g) was added and the reaction mixture was stirred at about 70 ℃ under reflux for 3 h. TLC (PE; EA ═ 5:1) reaction was complete, the reaction was also cooled and filtered, and the mother liquor was concentrated to give the crude product. The crude product was purified by Flash column chromatography (eluent: ethyl acetate/petroleum ether ═ 0% to 30%) to give 9.0g of intermediate II, yield 92.8%, yellow solid.
Example 2: synthesis of intermediate III
Figure RE-GDA0003090297040000042
8g of intermediate II was suspended and stirred in 6N HCl (100mL) aqueous solution, placed in an oil bath at 120 ℃ and stirred for about 1h, and the reaction was completed by TLC (PE: EA ═ 3: 1). Standing and cooling overnight, precipitating solid, filtering, drying to obtain 7.0g of intermediate III, yield 96.0%, white solid.
Example 3: synthesis of intermediate IV
Figure RE-GDA0003090297040000051
7.2g of intermediate III was dissolved in methanol (100mL) and sodium borohydride (3.0 eq, 5.8 g) was added portionwise at room temperature (possibly in an ice bath) to give a suspension. The reaction was carried out at room temperature for about 1.5 h. Water was added to quench the reaction, a small amount of potassium carbonate was added to adjust the pH to 10, and the mixture was extracted with dichloromethane about 3 times, and the organic phase was washed with saturated brine, dried, and concentrated to give about 5.5 g of intermediate IV in 91.7% yield as a yellow solid.
Example 4: Chloroproaline-D7Synthesis of (2)
Figure RE-GDA0003090297040000052
3 g of intermediate 4 was dissolved in methanol-D (30 mL), and acetone-D was added6(1.68 g,1.5 eq), and the reaction was stirred at room temperature for about 2 h. Sodium borodeuteride (1.2 g,1.5 eq) was added in portions in an ice bath, and after the addition was completed, the reaction was allowed to proceed overnight at room temperature. The reaction was quenched, extracted 3 times with dichloromethane, the organic phases combined, dried and concentrated. The crude product was purified by Flash column chromatography (eluent: dichloromethane: MeOH 10: 1) to give 3.1 g of chloropropaline-D7The yield is 81.0%, and the isotope abundance is 98.1% by MS detection.
Comparative example 1: preparation of Clontario-D7:
3 g of intermediate 4, acetone-D6 (1.68 g,1.5 eq) was dissolved in methanol-D (30 mL), sodium cyanoboroboron deuteride (1.73 g,1.5 eq) 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, saturated aqueous ammonium chloride solution and dichloromethane were added for extraction, dichloromethane was concentrated, and the crude product was purified by Flash column chromatography (eluent: dichloromethane: MeOH 10: 1) to give 2.7 g of chloropropaline-D7 in a yield of 70.5%, and a white solid was detected by MS to have an isotopic abundance of 98.0%.
Control group 1: synthesis of chlorpropaline
Figure RE-GDA0003090297040000053
3 g of intermediate 4 was dissolved in methanol (30 mL), acetone (1.5 g,1.5 eq) was added, and the reaction was stirred at room temperature for about 2 h. Sodium borohydride (1.0 g,1.5 eq) was added in portions in an ice bath, and after the addition was completed, the reaction was allowed to proceed overnight at room temperature. The reaction was quenched, extracted 3 times with dichloromethane, the organic phases combined, dried and concentrated. The crude product was purified by Flash column chromatography (eluent: dichloromethane: MeOH ═ 10: 1) to give 3.0g of chlorpropaline, yield 80.0%, white solid.
Experimental example 1
Molecular ion peak [ M + H ] detected by ESI-MS]+221.2, and the theoretical calculation result [ M + H ═]+221.1, with an isotopic abundance of 98.1%; through nuclear magnetic resonance analysis, compared with nuclear magnetic data of natural abundance chlorpropaline in a control group 1, 6 methyl hydrogens and 1 methine hydrogen in isopropylamine groups disappear due to being marked by D, hydrogen signals with chemical shifts of 1.12ppm and 2.96ppm disappear, nuclear magnetic signals of other hydrogen in the structure are basically consistent, the nuclear magnetic signals are consistent with a target structure, the structure is correct, and data are analyzed: 1H NMR (400MHz, Methanol-d4) δ 7.62(dd, J ═ 7.7,1.7Hz,1H), 7.41-7.30 (m,2H),7.26(dd, J ═ 7.6,1.8Hz,1H),5.19(dd, J ═ 9.6,2.8Hz, 1H),2.89(dd, J ═ 12.4,2.9Hz,1H),2.53(dd, J ═ 12.4,9.6Hz, 1H).
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 chlorpropaline is characterized by comprising the following steps: the method comprises the following steps:
(1) taking a compound I as a raw material, and carrying out nucleophilic substitution reaction with an amination reagent sodium diformylamide in an organic solvent to generate an intermediate compound II;
(2) synthesizing an intermediate compound III by a hydrolysis reaction of the intermediate compound II under an acidic condition;
(3) reacting the intermediate compound III in a solvent under the action of a reducing agent to obtain an intermediate IV;
(4) reacting the intermediate compound IV with stable isotope labeled acetone in a solvent under the action of a reducing agent to obtain a target compound V;
the reaction route is as follows:
Figure FDA0002997228430000011
2. the method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the organic solvent in the step (1) is tetrahydrofuran, acetonitrile or acetone, and more preferably, the organic solvent is acetonitrile.
3. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
in the step (1), the molar ratio of the compound I to the amination reagent is (1: 1) to (1: 5).
4. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the acidic condition in the step (2) is hydrochloric acid, a sulfuric acid reagent or an aqueous solution or an organic solution of the acidic reagent;
preferably, the acidic reagent in step (2) 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%.
5. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the solvent in the step (3) is methanol, ethanol, tetrahydrofuran or a mixed solvent of the above, more preferably, the solvent is methanol;
the reducing agent in the step (3) is sodium borohydride, potassium borohydride, diborane or hydrogen, preferably sodium borohydride.
6. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the molar ratio of the compound III to the reducing agent in the step (3) is (1: 1) to (1: 3), and more preferably, the molar ratio is (1: 3).
7. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the solvent in the step (4) is deuterated methanol, deuterated ethanol, tetrahydrofuran or a mixed solvent of the deuterated methanol and the deuterated ethanol, preferably deuterated methanol;
more preferably, the deuterated methanol in the step (4) is CH3OD or CD3OD, more preferably, the solvent is CH3OD。
8. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the isotope labeled acetone in the step (4) is acetone-D6Acetone-13C3Or acetone-2-13C；
The reducing agent in the step (4) is sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium deuteroborohydride, lithium aluminum hydride, potassium deuteroborohydride, hydrogen or deuterium; sodium deuteride or sodium borohydride is preferred.
9. The method for preparing chlorpropaline labeled with a stable isotope according to claim 1, wherein:
the molar ratio of the compound III to the reducing agent in the step (4) is (1: 1) to (1: 3), and more preferably (1: 1.5).
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Application publication date: 20210723