Preparation method of deuterated aromatic ring compound
By controlling the molar ratio and adjusting the reaction conditions in the heating and stirring reaction of aromatic ring compounds, promoter catalysts, alkalis and deuterium source reagents, the problems of high temperature and high pressure and metal catalyst dependence for the preparation of deuterated aromatic compounds in the prior art are successfully solved. A high yield, safe and environmentally friendly preparation of deuterated aromatic ring compounds is achieved.
Patent Information
- Application Number
- CN202411852593.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-16
- Publication Date
- 2025-02-18
AI Technical Summary
The methods for preparing deuterated aromatic compounds in the prior art usually require high temperature and high pressure conditions or rely on complex structures and expensive metal catalysts, and the reaction conditions are harsh and complex.
The preparation of deuterated aromatic ring compounds is achieved by controlling the molar ratio and adjusting the reaction conditions by heating and stirring of aromatic ring compounds, catalysts, alkalis and deuterium source reagents.
The process of this method is simple, does not require high temperature and high pressure conditions or metal catalysts, is safe and environmentally friendly, and the yield of deuterated aromatic ring compounds is high, reaching 89%, and has high economic value.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a deuterated aromatic ring compound. Background Art
[0002] In many organic molecules, when hydrogen atoms are replaced by deuterium atoms, their physical and chemical properties change, which is mainly attributed to the shorter bond length and higher bond energy of carbon-deuterium bonds compared to carbon-hydrogen bonds. In the field of spectrochemistry, deuterium-labeled compounds can be used as internal standards; in the field of pharmaceutical chemistry, the pharmacokinetic properties of drug molecules can be adjusted by changing the carbon-deuterium bond, thereby reducing toxic side effects; and in the field of optoelectronic materials, the carbon-deuterium bond provides a more stable rigid structure, which helps to extend the service life of the device.
[0003] Given the core position of aromatic ring compounds in complex drug molecules and optoelectronic materials, the development of efficient deuterium-hydrogen exchange reaction technology to prepare deuterated aromatic compounds has become a research hotspot. Currently, the methods for preparing deuterated aromatic compounds mainly include aromatic deoxygenation, dehalogenation, hydrogen-deuterium exchange, and unsaturated bond reduction, etc. These methods often rely on deuterium gas, toxic or flammable and explosive deuterium sources. In particular, the hydrogen-deuterium exchange process usually needs to be carried out under harsh conditions of high temperature and pressure, or relies on complex and expensive metal catalysts.
[0004] Chinese patent CN106928117 dissolves halogenated aromatic compounds and alkali metal salts MA in a deuterated solvent or a mixed solvent of a deuterated solvent and a conventional solvent, drops an organosilicon reagent, and reacts at -40°C to 150°C to obtain deuterated aromatic compounds; Chinese patent CN113149801 discloses direct deuterium-hydrogen exchange in polyhalogenated aromatic compounds using ordinary toluene as solvent and silver salt as catalyst. The methods disclosed in the above technologies have been greatly improved and studied, but the reaction conditions are still harsh and complicated. Summary of the invention
[0005] In order to solve the problems in the prior art, the present invention provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0006] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0007] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0008] S3, solution A is extracted, washed and spin-dried to obtain.
[0009] In one embodiment, the molar ratio of the aromatic ring compound, the base and the deuterium source is 1:(1.5-2):(1-1.5), which may be 1:1.5:1, 1:1.5:1.5, 1:1.5:2, 1:2:1, 1:2:1.5.
[0010] In a preferred embodiment, the molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0011] In one embodiment, the molar ratio of the aromatic ring compound to the promoting catalyst is 1:(0.05-0.1).
[0012] In a preferred embodiment, the molar ratio of the aromatic ring compound to the promoting catalyst is any one of 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, and 1:0.1.
[0013] In a more preferred embodiment, the molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.05.
[0014] In one embodiment, the structural formula of the aromatic ring compound is:
[0015] Wherein, R is selected from any one of an alkyl group, an aromatic group, an acyl group, and a hydrogen atom; and X is selected from any one of an iodine group, a bromine group, a chlorine group, and a trifluoromethanesulfonyl group.
[0016] In one embodiment, the deuterium source reagent includes any one of deuterated DMSO and heavy water.
[0017] In a preferred embodiment, the deuterium source reagent is deuterated DMSO.
[0018] In one embodiment, the promoting catalyst includes at least one of cuprous chloride, cupric oxide, and zinc oxide.
[0019] In a preferred embodiment, the promoting catalyst is cuprous chloride.
[0020] In one embodiment, the base is selected from at least one of an organic base and an inorganic base.
[0021] In one embodiment, the organic base includes at least one of triethylamine and pyridine.
[0022] In one embodiment, the inorganic base includes at least one of potassium carbonate and potassium hydroxide.
[0023] In a preferred embodiment, the base is potassium carbonate.
[0024] In one embodiment, the temperature of the S1 heating and stirring is 100°C.
[0025] In one embodiment, the temperature of heating and stirring in step S2 is 80-100°C.
[0026] In a preferred embodiment, the temperature of heating and stirring in step S2 is any one of 80°C, 90°C, and 100°C.
[0027] In a more preferred embodiment, the temperature of heating and stirring in step S2 is 100°C.
[0028] In one embodiment, the heating and stirring time in step S2 is 2-16 hours.
[0029] In a preferred embodiment, the heating and stirring time in step S2 is any one of 2h, 5h, 10h, 15h, and 16h.
[0030] In the present invention, LCMS is used to monitor the amount of aromatic ring compounds in the reaction system in step S2. When no aromatic ring compounds can be detected, the reaction is terminated.
[0031] In one embodiment, the step S3 is specifically as follows: solution A is extracted with ethyl acetate 2-3 times, washed with saturated brine, and spin-dried to obtain.
[0032] Beneficial Effects
[0033] 1. The preparation method of the deuterated aromatic ring compound provided by the present invention has a simple process and does not require harsh high temperature and high pressure reaction conditions or complex and expensive metal catalysts to prepare the deuterated aromatic ring compound.
[0034] 2. The preparation method of the deuterated aromatic ring compound provided by the present invention has good universality and is highly applicable to the preparation of raw material substrate aromatic ring compounds.
[0035] 3. The preparation method of the deuterated aromatic ring compound provided by the present invention does not involve deuterium gas, toxic or flammable and explosive deuterium sources, and is safe and environmentally friendly.
[0036] 4. The method for preparing deuterated aromatic ring compounds provided by the present invention controls the molar ratio of the aromatic ring compound, the base and the deuterium source reagent to be 1:2:1, and the yield of the deuterated aromatic ring compound can reach up to 89%.
[0037] 5. The preparation method of the deuterated aromatic ring compound provided by the present invention has high production efficiency and high economic value. DETAILED DESCRIPTION
[0038] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. The experimental methods in the examples without specifying specific conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without specifying the manufacturer are all conventional products that can be purchased commercially.
[0039] Example 1
[0040] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0041] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0042] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0043] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0044] The aromatic ring compound is bromobenzene, the promoting catalyst is copper oxide, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0045] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0046] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0047] The temperature of the S1 heating and stirring is 100°C.
[0048] The temperature of the S2 heating and stirring is 80°C.
[0049] The heating and stirring time in step S2 is 16 hours.
[0050] The stirring speed in steps S1 and S2 is 800 rpm.
[0051] Example 2
[0052] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0053] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0054] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0055] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0056] The aromatic ring compound is bromobenzene, the promoting catalyst is zinc oxide, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0057] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0058] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0059] The temperature of the S1 heating and stirring is 100°C.
[0060] The temperature of the S2 heating and stirring is 80°C.
[0061] The heating and stirring time in step S2 is 16 hours.
[0062] The stirring speed in steps S1 and S2 is 800 rpm.
[0063] Example 3
[0064] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0065] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0066] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0067] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0068] The aromatic ring compound is bromobenzene, the promoting catalyst is cuprous chloride, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0069] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0070] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0071] The temperature of the S1 heating and stirring is 100°C.
[0072] The temperature of the S2 heating and stirring is 80°C.
[0073] The heating and stirring time in step S2 is 16 hours.
[0074] The stirring speed in steps S1 and S2 is 800 rpm.
[0075] Example 4
[0076] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0077] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0078] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0079] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0080] The aromatic ring compound is bromobenzene, the promoting catalyst is cuprous chloride, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0081] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0082] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0083] The temperature of the S1 heating and stirring is 100°C.
[0084] The temperature of the S2 heating and stirring is 100°C.
[0085] The heating and stirring time in step S2 is 16 hours.
[0086] The stirring speed in steps S1 and S2 is 800 rpm.
[0087] Example 5
[0088] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0089] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0090] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0091] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0092] The aromatic ring compound is bromobenzene, the promoting catalyst is cuprous chloride, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0093] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0094] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0095] The temperature of the S1 heating and stirring is 100°C.
[0096] The temperature of the S2 heating and stirring is 100°C.
[0097] The heating and stirring time in step S2 is 2 hours.
[0098] The stirring speed in steps S1 and S2 is 800 rpm.
[0099] Example 6
[0100] This embodiment provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0101] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0102] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0103] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0104] The aromatic ring compound is bromobenzene, the promoting catalyst is cuprous chloride, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0105] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0106] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.05.
[0107] The temperature of the S1 heating and stirring is 100°C.
[0108] The temperature of the S2 heating and stirring is 100°C.
[0109] The heating and stirring time in step S2 is 16 hours.
[0110] The stirring speed in steps S1 and S2 is 800 rpm.
[0111] Example 7
[0112] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the aromatic ring compound in this embodiment is iodobenzene.
[0113] Example 8
[0114] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the aromatic ring compound in this embodiment is trifluorotoluenesulfonic acid.
[0115] Example 9
[0116] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the aromatic ring compound in this embodiment is chlorobenzene.
[0117] Example 10
[0118] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0119] Embodiment 11
[0120] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0121] Example 12
[0122] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0123] Example 13
[0124] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0125] Embodiment 14
[0126] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0127] Embodiment 15
[0128] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0129] Example 16
[0130] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0131] Embodiment 17
[0132] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0133] Embodiment 18
[0134] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0135] Embodiment 19
[0136] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is
[0137] Embodiment 20
[0138] The specific implementation of this embodiment is the same as that of Embodiment 6, except that the structural formula of the aromatic ring compound in this embodiment is Comparative Example 1
[0139] This comparative example provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0140] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0141] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0142] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0143] The aromatic ring compound is bromobenzene, the promoting catalyst is copper oxide, the base is triethylamine, and the deuterium source reagent is heavy water.
[0144] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0145] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0146] The temperature of the S1 heating and stirring is 100°C.
[0147] The temperature of the heating and stirring of S2 is 20°C.
[0148] The heating and stirring time in step S2 is 16 hours.
[0149] The stirring speed in steps S1 and S2 is 800 rpm.
[0150] Comparative Example 2
[0151] This comparative example provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0152] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0153] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0154] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0155] The aromatic ring compound is bromobenzene, the promoting catalyst is copper oxide, the base is pyridine, and the deuterium source reagent is heavy water.
[0156] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0157] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0158] The temperature of the S1 heating and stirring is 100°C.
[0159] The temperature of the heating and stirring of S2 is 20°C.
[0160] The heating and stirring time in step S2 is 16 hours.
[0161] The stirring speed in steps S1 and S2 is 800 rpm.
[0162] Comparative Example 3
[0163] This comparative example provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0164] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0165] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0166] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0167] The aromatic ring compound is bromobenzene, the promoting catalyst is copper oxide, the base is potassium carbonate, and the deuterium source reagent is heavy water.
[0168] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0169] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0170] The temperature of the S1 heating and stirring is 100°C.
[0171] The temperature of the heating and stirring of S2 is 20°C.
[0172] The heating and stirring time in step S2 is 16 hours.
[0173] The stirring speed in steps S1 and S2 is 800 rpm.
[0174] Comparative Example 4
[0175] This comparative example provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0176] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0177] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0178] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0179] The aromatic ring compound is bromobenzene, the promoting catalyst is copper oxide, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0180] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0181] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0182] The temperature of the S1 heating and stirring is 100°C.
[0183] The temperature of the heating and stirring of S2 is 20°C.
[0184] The heating and stirring time in step S2 is 16 hours.
[0185] The stirring speed in steps S1 and S2 is 800 rpm.
[0186] Comparative Example 5
[0187] This comparative example provides a method for preparing a deuterated aromatic ring compound, comprising the following steps:
[0188] S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A;
[0189] S2, heating, stirring and filtering the reaction product to obtain solution A;
[0190] S3. Solution A was extracted twice with ethyl acetate, washed with saturated brine, and dried by rotation to obtain.
[0191] The aromatic ring compound is bromobenzene, the promoting catalyst is potassium hydroxide, the base is potassium carbonate, and the deuterium source reagent is deuterated DMSO.
[0192] The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:2:1.
[0193] The molar ratio of the aromatic ring compound to the promoting catalyst is 1:0.1.
[0194] The temperature of the S1 heating and stirring is 100°C.
[0195] The temperature of the S2 heating and stirring is 80°C.
[0196] The heating and stirring time in step S2 is 16 hours.
[0197] The stirring speed in steps S1 and S2 is 800 rpm.
[0198] Performance Testing
[0199] The yields of the deuterated aromatic ring compounds prepared in various examples and comparative examples are listed in Table 1.
[0200] Table 1
[0201]
[0202]
Claims
1. A method for preparing a deuterated aromatic ring compound, characterized in that: The following steps are involved: S1, heating and stirring an aromatic ring compound, a promoting catalyst, a base and a deuterium source reagent to obtain a reaction product A; S2, heating, stirring and filtering the reaction product to obtain solution A; S3, solution A is extracted, washed and spin-dried to obtain.
2. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The molar ratio of the aromatic ring compound, the base and the deuterium source reagent is 1:(1.5-2):(1-1.5).
3. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The structural formula of the aromatic ring compound is: Wherein, R is selected from any one of an alkyl group, an aromatic group, an acyl group, and a hydrogen atom; and X is selected from any one of an iodine group, a bromine group, a chlorine group, and a trifluoromethanesulfonyl group.
4. The method for preparing a deuterated aromatic ring compound according to claim 3, characterized in that: The aromatic ring compound includes any one of trifluorotoluenesulfonic acid, iodobenzene, bromobenzene and chlorobenzene.
5. The method for preparing a deuterated aromatic ring compound according to any one of claims 1 to 4, characterized in that: The deuterium source reagent includes any one of deuterated DMSO and heavy water.
6. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The promoting catalyst includes at least one of cuprous chloride, cupric oxide and zinc oxide.
7. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The base is selected from at least one of an organic base and an inorganic base.
8. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The temperature of heating and stirring in the step S2 is 80-100°C.
9. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The heating and stirring time in step S2 is 2-16 hours.
10. The method for preparing a deuterated aromatic ring compound according to claim 1, characterized in that: The S3 step is specifically as follows: solution A is extracted with ethyl acetate for 2-3 times, washed with saturated brine, and spin-dried to obtain the product.