A green synthesis method for preparing deuterated compounds under light irradiation

Abstract

The present invention discloses a green synthesis method for preparing deuterated compounds under illumination, comprising the steps of mixing an aromatic compound, a nitrogen-containing heterocycle, a boron reagent, a base, a deuterium transfer reagent, and a deuterated reagent, stirring, and reacting under illumination. The present invention employs a synergistic catalytic strategy of photocatalysis and organic small molecules, eliminating the need for an external photocatalyst. Single electron transfer can be directly performed using self-assembled electron donor-acceptor complexes. Furthermore, the method features mild reaction conditions, a low-cost deuterium source, high deuterium incorporation, high selectivity, and good functional group tolerance.

Description

Technical Field

[0001] The present invention relates to the field of organic compound synthesis, and in particular to a green synthesis method for preparing deuterated compounds under light irradiation. Background Art

[0002] Deuterium is a stable and non-radioactive isotope of hydrogen. Deuterium labeling is widely used as an effective tool for studying the absorption, distribution, metabolism, and excretion (ADME) of drugs in the biomedical field. Furthermore, in the pharmaceutical industry, selective incorporation of deuterium sites into drug molecules can mitigate potential diastereoisomerization in drug metabolism, thereby improving drug efficacy. Furthermore, the US Food and Drug Administration approved the first deuterated drug, deutetrabenazine, in 2017, further spurring the development of novel deuterated methods.

[0003] Due to the importance of deuterated compounds, chemists have developed various deuteration reactions. The basic methods for incorporating deuterium into organic molecules are (1) ionic strategies: Traditional ionic strategies involve the use of strong deuterated acids or bases such as DCl, D2SO4 or NaOD to induce H / D exchange. However, due to the need to use strong acids and strong bases, this leads to significant safety risks, and this deuteration method usually results in poor functional group tolerance and uncontrolled chemical selectivity. (2) Transition metal catalytic methods: such as H / D exchange catalyzed by transition metals Ir, Pd, Pt, Ru or Rh, but transition metal catalysis usually requires the co-catalysis of directing groups. Directing groups are generally relatively stable CC / CO / CN bonds, and it is difficult to remove directing groups. In addition, in reports of transition metal catalysis without directing groups, special substrates are generally required, and the regioselectivity is poor. On the other hand, most of these transition metals are expensive, and some metal complexes are sensitive to water and air. In the pharmaceutical and materials industries, in order to solve the "transition metal residue problem", complex post-processing procedures are required, which consumes a lot of energy. In recent years, photocatalysis has become a powerful tool in synthetic chemistry, especially for the selective activation of inert chemical bonds under mild conditions, providing a method for obtaining the corresponding deuterated products of chemicals and drugs in a mild and controllable manner. Summary of the Invention

[0004] In order to overcome the shortcomings of traditional deuteration strategies, a green synthesis method for preparing deuterated compounds under light is provided, which has mild reaction conditions, good selectivity, low cost, good functional group tolerance, and complies with the concept of green chemistry, environmental protection and energy saving.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is:

[0006] The first aspect of the present invention provides a green synthesis method for preparing a deuterated compound under light irradiation, comprising mixing an aromatic compound, a nitrogen-containing heterocycle, a diboron reagent, a base, a deuterium transfer reagent, and a deuterated reagent, stirring, and reacting under light; the aromatic compound has the structural formula:

[0007]

[0008] Wherein, R1, R2, R3, R4 and R5 are the same or different C1-C 20 Alkyl, C1-C 20 Heteroalkyl, C3-C 20 Cycloalkyl, C3-C 20 Heterocycloalkyl, C2-C 20 Alkenyl, C2-C 20 Heteroalkenyl, C3-C 20 Cycloalkenyl, C3-C 20 Heterocycloalkenyl, C2-C 20 Alkynyl, C2-C 20 Heteroalkynyl, C3-C 20 Cycloalkynyl, C3-C 20 Heterocycloalkynyl, C1-C 20 Alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, heteroaryloxy, aryl (C1-C 20 )alkyl, heteroaryl (C1-C 20 ) alkyl, C2-C 20 Alkenyl (C1-C 20 ) alkyl, C2-C 20 Alkynyl (C1-C 20 )alkyl, cyano (C1-C 20 ) alkyl, alkyloxycarbonylalkyl, or a hydrogen atom substituent.

[0009] Preferably, the aromatic compound includes at least one of 1-bromo-3,5-dimethoxybenzene, 1-bromo-3,4,5-trimethoxybenzene, 4-bromobenzaldehyde dimethyl acetal, 1-bromo-5-isopropyl-4-methoxy-2-methylbenzene, and 4-bromo-5-methyl-2-(prop-2-yl)phenol.

[0010] Preferably, the nitrogen-containing heterocycle is at least one of the following compounds:

[0011]

[0012] Wherein, EDG represents an electron-donating group, including dialkylamino, alkylamino, amino, hydroxyl, alkoxy, amide, acyloxy, alkyl, carboxymethyl, and phenyl;

[0013] Among them, EWG represents an electron-withdrawing group, including tertiary amine cation, nitro group, trifluoromethyl group, cyano group, sulfonic acid group, formyl group, acyl group, and carboxyl group.

[0014] More preferably, the nitrogen-containing heterocycle is isoquinoline

[0015] Preferably, the biboron reagent is at least one of the following compounds:

[0016]

[0017] More preferably, the diboron reagent is diboric acid pinacol ester

[0018] Preferably, the base is at least one of TEA, K2CO3, Li2CO3, Na3PO4, and CS2CO3; further preferably, the base is cesium carbonate (CS2CO3).

[0019] Preferably, the deuterium transfer reagent is at least one of the following compounds:

[0020]

[0021] Further preferably, the deuterium transfer reagent is tert-butyl mercaptan

[0022] Preferably, the deuterated reagent is at least one of CD3OD, CD3CN, DMSO-d6, D2O, CDCl3, and C3D6O; further preferably, the deuterated reagent is deuterated methanol (CD3OD).

[0023] Preferably, the ratio of the aromatic compound to the deuterated reagent is 1 mmol: (2-3) mL.

[0024] Preferably, the wavelength of the light is 380-456 nm.

[0025] In some preferred embodiments of the present invention, the light source used for the illumination is a Kessil lamp, and the wavelength of the illumination is 390 nm.

[0026] Preferably, the stirring is magnetic rotor stirring; the reaction time is 22 to 26 hours; further preferably, the reaction time is 23 to 25 hours.

[0027] In some specific embodiments of the present invention, after the reaction is completed, the mixture is extracted with ethyl acetate, the organic phases are combined, dried, filtered, the filtrate is spin-dried, and separated by column chromatography to obtain the target product.

[0028] Preferably, the molar ratio of the aromatic compound, the nitrogen-containing heterocycle, the biboron reagent, the base and the deuterium transfer reagent is (1-100):(0.2-20):(0.2-20):(4-400):(0.2-20).

[0029] A second aspect of the present invention provides a deuterated compound, which is prepared by the green synthesis method for preparing a deuterated compound under light irradiation.

[0030] The third aspect of the present invention provides the use of the deuterated compound in the preparation of pharmaceutical intermediates.

[0031] Preferably, in the application, the pharmaceutical intermediate is thymol and its derivatives.

[0032] Compared with the prior art, the present invention has the following beneficial effects:

[0033] 1. The reaction system is simple and does not require the pre-preparation of complex photocatalysts. It relies on the self-assembly of the components in the system to produce an excited electron donor-acceptor complex with a strong single-electron supply capacity, which simplifies the operation during the preparation and production process, is economical and environmentally friendly, and the reaction process is safe and controllable.

[0034] 2. Using blue LEDs as reaction energy is green and environmentally friendly with high energy utilization rate, and can efficiently realize the conversion of light energy into chemical energy.

[0035] 3. The reactant raw materials and deuterium source required in the reaction system are cheap and easy to obtain, and can be directly used for preparation and production without additional modification, which simplifies the operation steps, shortens the reaction route, and significantly reduces production costs.

[0036] 4. The required reaction conditions are mild, the process is economically efficient, and it has good prospects for industrial application. Due to the progressive nature of the present invention's green synthesis method for synthesizing deuterated compounds under illumination, it can be widely used in the fields of medicine and synthetic industries, effectively reducing economic costs and improving its environmental friendliness. DETAILED DESCRIPTION

[0037] The following is a further description of specific embodiments of the present invention. It should be noted that the description of these embodiments is intended to facilitate understanding of the present invention and does not constitute a limitation of the present invention. In addition, the technical features involved in the various embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.

[0038] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified.

[0039] The compounds and their derivatives involved in the examples of the present invention are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, located in Columbus, Ohio) nomenclature system.

[0040] Example 1

[0041] This embodiment provides a green synthesis method for preparing a deuterated compound under light irradiation, which specifically includes the following steps:

[0042] To a dry 2 mL vial, 1-bromo-3,5-dimethoxybenzene (0.2 mmol, 1.0 eq), isoquinoline (0.04 mmol, 0.2 eq), pinacol diboron (0.04 mmol, 0.2 eq), cesium carbonate (0.8 mmol, 4 eq), tert-butyl mercaptan (0.04 mol, 0.2 eq), and deuterated methanol (0.5 mL) were added. The vial was sealed and stirred at room temperature until uniform. The mixture was then stirred on a stirrer and irradiated with 390 nm LEDs for 24 hours. After completion of the reaction, the mixture was extracted with ethyl acetate, the combined organic phases were dried, filtered, and the filtrate was spin-dried to dryness. The desired product was obtained with a deuterated yield of 94.51% and a deuterated fraction of 85%.

[0043] product: 1,3-dimethoxybenzene-5-d

[0044] 26.31mg,94.51%yield.85%D-inc. 1 H NMR (400MHz, Chloroform-d) δ7.18 (t, J = 8.2 Hz, 0.15H), 6.51 (d, J = 1.2 Hz, 2H), 6.47 (t, J = 2.4 Hz, 1H), 3.79 (s, 6H). 13 C NMR (151MHz, Chloroform-d) δ160.90,129.84,106.20,100.4,55.30.

[0045] Example 2

[0046] The preparation method of this example was similar to that of Example 1, except that 1-bromo-3,4,5-trimethoxybenzene (0.2 mmol) was used instead of 1-bromo-3,5-dimethoxybenzene. After the reaction, extraction was performed with ethyl acetate, the combined organic phases were dried, filtered, and the filtrate was spin-dried and separated by column chromatography. The deuterated yield was 74%, and the deuterated rate was 84%.

[0047] product: 1,2,3-trimethoxybenzene-5-d

[0048] 25.04mg 74%yield.84%D-inc. 1 H NMR (400MHz, Chloroform-d) δ6.98 (t, J = 8.4Hz, 0.16H), 6.57 (s, 2H), 3.85 (s, 6H), 3.84 (s, 3H). 13 C NMR (151MHz, Chloroform-d) δ153.6,138.4,123.7,105.4,60.9,56.7.

[0049] Example 3

[0050] The preparation method of this example was similar to that of Example 1, except that 4-bromobenzaldehyde dimethyl acetal (0.2 mmol) was used instead of 1-bromo-3,5-dimethoxybenzene. After the reaction, extraction was performed with ethyl acetate. The combined organic phases were dried, filtered, and the filtrate was spin-dried and separated by column chromatography to obtain the desired product with a deuterated yield of 84% and a deuterated rate of 88%.

[0051] product: 1-(dimethoxymethyl)benzene-4-d

[0052] 25.73mg,84%yield.88%D-inc. 1 H NMR(400MHz,Chloroform-d)δ7.49–7.42(m,2H),7.38–7.34(m,2H),7.32(s,0.12H),5.39(s,1H),3.32(s,6H).13C NMR(151MHz,Chloroform-d)δ138.0,128.4,128.2,126.7,103.1,52.6.

[0053] Example 4

[0054] The preparation method of this example is similar to that of Example 1, except that 1-bromo-5-isopropyl-4-methoxy-2-methylbenzene (0.2 mmol) is used instead of 1-bromo-3,5-dimethoxybenzene. After the reaction is completed, the mixture is extracted with ethyl acetate, the organic phases are combined and dried, filtered, the filtrate is spin-dried, and column chromatography is performed to obtain the target product with a deuterated yield of 45% and a deuterated rate of 64%.

[0055] product: 1-isopropyl-2-methoxy-4-methylbenzene-5-d

[0056] 14.87mg, 45% yield, 64% D-inc.1 H NMR (400MHz, Chloroform-d) δ7.09 (s, 1H), 6.75 (d, J = 7.8HZ, 0.36H), 6.67 (s, 1H), 3.81 (s, 3H), 3.26 (m, 1H), 2.33 (s, 3H), 1.18 (d, J = 6.8Hz, 6H). 13 C NMR (151MHz, Chloroform-d) δ156.5,135.4,133.1,125.8,121.1,110.5,54.5.26.5,23.1,21,4.

[0057] Example 5

[0058] The preparation method of this example was similar to that of Example 1, except that 4-bromo-5-methyl-2-(propan-2-yl)phenol (CAS: 15062-34-7) (0.2 mmol) was used instead of 1-bromo-3,5-dimethoxybenzene. After the reaction, extraction was performed with ethyl acetate. The combined organic phases were dried and filtered. The filtrate was spin-dried, separated by column chromatography, and concentrated under reduced pressure to obtain the desired product. The deuterated yield was 27% and the deuterated rate was 67%.

[0059] product: 2-isopropyl-5-methylphen-4-d-ol

[0060] 8.17mg, 27% yield, 67% D-inc. 1 H NMR(400MHz,Chloroform-d)δ7.08(s,1H),6.72(d,J=7.9Hz,0.33H),6.58(s,1H),3.25–3.15(m,1H),2.26(s,3 H),1.23(s,6H).13CNMR(151MHz,Chloroform-d)δ152.7,136.7,131.8,126.4,122.1,116.3,27.3,22.9,21.1.

[0061] The embodiments of the present invention are described in detail above, but the present invention is not limited to the described embodiments. It is apparent to those skilled in the art that various changes, modifications, substitutions, and variations of these embodiments may be made without departing from the principles and spirit of the present invention, and the changes still fall within the scope of protection of the present invention.

Claims

1. A green synthesis method for preparing deuterated compounds under light irradiation, characterized in that: The aromatic compound, the nitrogen-containing heterocycle, the biboron reagent, the base, the deuterium transfer reagent and the deuterated reagent are mixed, stirred, and reacted under light; The aromatic compound includes at least one of 1-bromo-3,5-dimethoxybenzene, 1-bromo-3,4,5-trimethoxybenzene, 4-bromobenzaldehyde dimethyl acetal, 1-bromo-5-isopropyl-4-methoxy-2-methylbenzene, and 4-bromo-5-methyl-2-(prop-2-yl)phenol; The nitrogen-containing heterocycle is isoquinoline; The boron reagent is pinacol borate; The base is cesium carbonate; The deuterium transfer reagent is tert-butyl mercaptan; The deuterated reagent is deuterated methanol.

2. The green synthesis method for preparing deuterated compounds under light according to claim 1, characterized in that: The wavelength of the light is 380-456 nm.

3. The green synthesis method for preparing a deuterated compound under light according to any one of claims 1 to 2, characterized in that: The molar ratio of the aromatic compound, the nitrogen-containing heterocycle, the biboron reagent, the base and the deuterium transfer reagent is (1-100): (0.2-20): (0.2-20): (4-400): (0.2-20).

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