Preparation method of indazole synthetic cannabinoid deuterated internal standard substance

Abstract

The invention provides a preparation method of an indazole synthetic cannabinoid deuterated internal standard substance, and relates to the technical field of cannabinoid deuterated internal standard substances, and the preparation method comprises the following steps: 1, reacting aniline-D5 with chloral hydrate and hydroxylamine hydrochloride in a sodium sulfate aqueous solution to generate a compound 1; step 2, performing acid action on the compound 1 to generate a compound 2; 3, carrying out ring opening, diazotization, reduction and cyclization on the compound 2 to form a compound 3; 4, reacting the compound 3 with halogenated alkane under an alkaline condition to generate a compound 4; 5, the compound 4 and an amine compound are subjected to an amide condensation reaction, and the indazole synthetic cannabinoid deuterated internal standard substance is obtained. The raw materials are cheap and easy to obtain, and the preparation method is simple, so that the purpose of green and safe preparation of the indazole synthetic cannabinoid deuterated internal standard substance is achieved, and powerful support is provided for judicial expertise and drug banning work.

Description

Technical Field

[0001] This invention relates to the field of cannabinoid deuterated internal standards, specifically a method for preparing an indazole-based synthetic cannabinoid deuterated internal standard. Background Technology

[0002] Indazole synthetic cannabinoids, due to their higher affinity for CB1 / CB2 receptors and sustained psychoactive activity, have become the fastest-growing new psychoactive substances (NPS) globally. Minor structural modifications to these compounds can circumvent regulations, rendering traditional immune screening ineffective, thus necessitating precise quantitative methods based on LC-HRMS / MS.

[0003] Stable isotope dilution is widely recognized as the "gold standard" for accurately determining trace NPS. Common stable isotopes include deuterium, 13 carbon, 15 Nitrogen and 18 Oxygen, etc. Deuterium has a very low abundance in nature, approximately 0.0156%. 13 The abundance of carbon is 1.11%. 15 The abundance of nitrogen is 0.366%. 18 Oxygen abundance is 0.2%, so the background signal of deuterated internal standards can be ignored; secondly, the mass of deuterium is about twice that of hydrogen, and this mass difference is easier to distinguish, resulting in a clearer signal; therefore, deuterated internal standards are the most widely used.

[0004] CN115784994A reports a method for preparing deuterated internal standards of indazole-based synthetic cannabinoids. The method involves a five-step reaction process using D6-indazole as the raw material, including iodination, carbon monoxide insertion, ester hydrolysis, N-alkylation, and amide condensation. However, D6-indazole is difficult to obtain, and carbon monoxide is a highly toxic gas, making this route neither economical nor environmentally friendly.

[0005] Therefore, developing a method for preparing deuterated internal standards of indazole synthetic cannabinoids using inexpensive, readily available, green, and safe raw materials is one of the problems that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0006] This invention provides a method for preparing a deuterated internal standard of indazole synthetic cannabinoids to solve the technical problems mentioned in the background art.

[0007] To address the aforementioned technical problems, this invention discloses a method for preparing a deuterated internal standard of indazole-based synthetic cannabinoids, comprising: Step 1: Aniline-D5 reacts with chloral hydrate and hydroxylamine hydrochloride in an aqueous sodium sulfate solution to generate compound 1; Step 2: Compound 1 is reacted with acid to form compound 2; Step 3: Compound 2 undergoes ring-opening, diazotization, reduction, and cyclization to form compound 3; Step 4: Compound 3 reacts with a haloalkane under alkaline conditions to generate compound 4; Step 5: Compound 4 undergoes an amide condensation reaction with an amine compound to obtain an indazole-based deuterated internal standard for synthetic cannabinoids.

[0008] The preferred structural formula of the indazole synthetic cannabinoid deuterated internal standard is as follows: .

[0009] Preferably, R1 in the structural formula of the indazole synthetic cannabinoid deuterated internal standard is any one of the following: .

[0010] Preferably, R2 in the structural formula of the indazole synthetic cannabinoid deuterated internal standard is any one of the following: .

[0011] Preferably, the synthetic route includes steps 1 to 5: .

[0012] Preferably, the acid in step 2 includes any one of concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, trifluoroacetic acid, acetic acid, propionic acid, and butyric acid.

[0013] Preferably, the alkali in step 4 includes any one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen hydride, butyllithium, lithium bis(trimethylsilylamino)amine, sodium bis(trimethylsilylamino)amine, and potassium bis(trimethylsilylamino)amine.

[0014] Preferably, step 01 is performed before the batch of raw materials in step 1 of the current batch is processed. Step 01 includes: Step 011: Determine the key raw material parameters of the raw materials in the current batch of Step 1 based on the detection. The key raw material parameters include: the crystallinity coefficient of aniline-D5. Step 012: Obtain the baseline reaction temperature range for each reaction stage under the raw material composition conditions of the current batch Step 1, and the fitting curve of the first reaction temperature - baseline equilibrium constant for each reaction stage under the same raw material composition conditions of the current batch Step 1; the first reaction temperature is selected from the corresponding baseline reaction temperature range according to the preset temperature gradient. Step 013: Obtain the benchmark key reaction parameters corresponding to each first reaction temperature. The benchmark key reaction parameters include: the benchmark resistance fluctuation coefficient and the benchmark reaction rate coefficient for each reaction stage. Step 014: Based on steps 012 and 013, select the target first reaction temperature for each reaction stage; Step 015: Based on the crystallinity coefficient of aniline-D5 obtained in Step 011, the target first reaction temperature for each reaction stage is corrected to obtain the second reaction temperature for each reaction stage; Step 016: Conduct reaction tests at the second reaction temperature of each reaction stage, and determine the actual resistance fluctuation coefficient and actual reaction rate coefficient, the actual equilibrium constant when the reaction reaches equilibrium, and the side reaction inhibition coefficient for each reaction stage; Step 017: Based on step 016, correct the second reaction temperature of each reaction stage to obtain the target reaction temperature of each reaction stage.

[0015] Preferably, step 1 is divided into two reaction stages: the induction reaction stage and the main reaction stage.

[0016] Preferably, the reaction process in step 2 is divided into several consecutive reaction periods, each corresponding to a baseline reaction temperature range; during batch reaction, each reaction period reacts at the corresponding target temperature. Before performing batch step 2 using the current batch of acid, step 02 is performed. Step 02 includes: Step 021 also obtains: baseline data on the initial reaction period of the current batch of acid with compound 1; Step 022: Sample the current batch of acid and compound 1 and conduct an initial reaction with the initial reaction period controlled by the baseline isothermal value. Perform multiple pH and temperature measurements to determine the actual carbon-deuterium bond retention state and the actual acid-deuterium perturbation state. Step 023: Based on the actual carbon-deuterium bond retention state value, the actual acid-deuterium perturbation state value, and the initial reaction temperature-compound 1 baseline conversion fitting curve, the baseline isothermal value of the initial reaction period is corrected to obtain the target temperature of the initial reaction period; Step 024: Determine the temperature inertia coefficient of the previous reaction period; Step 025: Determine the target temperature of the next reaction period based on the temperature inertia coefficient of the previous reaction period, the median of the target temperature difference range between the previous and next reaction periods, the inter-period temperature fluctuation coefficient between the previous and next reaction periods, and the target temperature of the previous reaction period. Repeat steps 024-025 until the target temperature for all reaction periods has been determined.

[0017] Preferably, step 021 also obtains: the baseline data for the initial reaction period of the same acid in the current batch with compound 1: the fitting curve of the reaction temperature-baseline conversion rate of compound 1 during the initial reaction period, the baseline isothermal value, and the range of target temperature difference values ​​with the next reaction period; Step 022 includes: Step 022a: In the preliminary experiment, add the current batch of acid and compound 1 according to the settings, inject them into the reaction vessel; use the initial reaction temperature as the reference constant temperature value of the initial reaction period, and stir with a stirring device; Step 022b: A distributed pH sensor array installed on the inner wall of the reaction vessel synchronously collects pH values ​​from different areas; Step 022c: The control unit compares the pH change curve from step 022b with the reference pH change curve and determines the actual carbon-deuterium bond retention state value by the difference in curve slope. Step 022d: Based on the real-time pH data from step 022b, determine the actual acid-deuterium perturbation state value based on the pH fluctuation amplitude.

[0018] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The raw materials are cheap and readily available, lowering the cost threshold: Aniline-D5 is used as the starting material (replacing the "difficult-to-obtain D6-indazole" in the background technology). Aniline-D5 is a common deuterated reagent in the chemical industry (easy to purchase on the market, and the price is only 1 / 3 to 1 / 2 of D6-indazole). In addition, chloral hydrate, hydroxylamine hydrochloride, sodium sulfate and other materials are all common chemical raw materials (low purchase cost and stable supply). This solves the pain point of "difficult-to-obtain raw materials" from the source, reducing the cost of raw materials per batch.

[0020] The process is green and safe, avoiding high-risk reagents: No highly toxic gases (such as carbon monoxide) are used throughout the process: Step 3 adopts a series process of "ring opening-diazotization-reduction-cyclization" to replace the "carbon monoxide carbonyl insertion reaction" in the background technology, eliminating the risk of highly toxic raw materials; at the same time, the acid reaction in Step 2 and the alkaline conditions in Step 4 are mild reaction environments (no need for high temperature and high pressure), and the amount of waste gas / waste liquid generated is reduced compared with the traditional route, which is in line with "green chemical industry".

[0021] This invention uses aniline-D5 as a raw material, and through a multi-step reaction, obtains the key intermediate indazole-3-carboxylic acid-D4. This intermediate is first alkylated with a haloalkane, and then undergoes an amide condensation reaction with an amine compound to obtain a deuterated internal standard for indazole synthetic cannabinoids. The raw materials used in this invention are inexpensive and readily available, and the preparation method is simple, thus achieving the goal of green and safe preparation of deuterated internal standards for indazole synthetic cannabinoids, providing strong support for forensic identification and drug control work. Attached Figure Description

[0022] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings: Figure 1 This is a flowchart of the present invention; Figure 2 Compound 6 (N-[[1-(4-penten-1-yl)-1) H The proton NMR spectrum of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4); Figure 3 Compound 6 (N-[[1-(4-penten-1-yl)-1) H Carbon NMR spectrum of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4); Figure 4 Compound 8 (N-[[1-(5-fluoropentyl)-1 H The proton NMR spectrum of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4); Figure 5 Compound 8 (N-[[1-(5-fluoropentyl)-1 H Carbon NMR spectrum of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4); Figure 6 Compound 9 (1-(5-fluoropentyl)-N-(1-methyl-1-phenylethyl)-1 H The proton NMR spectrum of (-indazole-3-formamide-D4); Figure 7 Compound 9 (1-(5-fluoropentyl)-N-(1-methyl-1-phenylethyl)-1 H Carbon NMR spectrum of (-indazole-3-carboxamide-D4); Figure 8 Compound 11 (N-(1-methyl-1-phenylethyl)-(4-cyanobutyl)-1 H The proton NMR spectrum of (-indazole-3-formamide-D4); Figure 9 Compound 11 (N-(1-methyl-1-phenylethyl)-(4-cyanobutyl)-1 H Carbon NMR spectrum of (-indazole-3-carboxamide-D4); Figure 10 Compound 13 (2-[1-(4-fluorobutyl)-1) H The proton NMR spectrum of methyl 3,3-dimethylbutyrate (D4) of [-indazole-3-formylamino]-3,3-dimethylbutyrate; Figure 11 Compound 13 (2-[1-(4-fluorobutyl)-1) H Carbon NMR spectrum of [-indazole-3-formylamino]-3,3-dimethylbutyrate methyl ester-D4). Detailed Implementation

[0023] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0024] Furthermore, in this invention, the use of terms such as "first" and "second" is for descriptive purposes only and does not specifically refer to any order or sequence, nor is it intended to limit the invention. They are merely used to distinguish components or operations described using the same technical terms and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined with "first" or "second" may explicitly or implicitly include at least one of those features. Additionally, the technical solutions and features of the various embodiments can be combined with each other, but this must be based on the ability of those skilled in the art to implement them. If a combination of technical solutions is contradictory or impossible to implement, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection claimed by this invention.

[0025] Combination Figures 1-11 The present invention provides the following embodiments: Example 1: Compound 6 (N-[[1-(4-penten-1-yl)-1 H Preparation method of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4):

[0026] Step 1) Preparation of Compound 1 (2-(hydroxyethylamine)-N-benzene-D4 acetamide): Chloral hydrate (10 g, 0.06 mol) was dissolved in 75 mL of water, and sodium sulfate (50 g, 0.35 mol) was added in portions at 50 °C, stirring until completely dissolved. Aniline-D5 (4.91 g, 0.05 mol) was dissolved in 6 M hydrochloric acid aqueous solution (10 mL) and slowly added dropwise to the mixed solution. Then, hydroxylamine hydrochloride (10.5 g, 0.15 mol) was dissolved in a small amount of water and added dropwise to the reaction solution. The temperature was raised to 80-90 °C and reacted for 2 h. After slow cooling, the mixture was filtered, and the solid was washed with a large amount of water and dried to obtain crude compound 1.

[0027] Step 2) Preparation of compound 2 (indigo-D4): Add 25 mL of concentrated sulfuric acid to a three-necked flask and heat to 60 °C. Add compound 1 to the concentrated sulfuric acid and keep the temperature below 65 °C. After reacting for 30 min, heat to 85 °C and react for 15 min. Slowly cool to room temperature and slowly pour the reaction solution into ice water. After stirring for a period of time, a large amount of solid precipitates out. Filter, wash with ice water, collect the solid and dry to obtain compound 2 (5.7 g, total yield of two steps 75%).

[0028] Step 3) Preparation of compound 3 (indazole-3-carboxylic acid-D4): Compound 2 (15.1 g, 0.1 mol) was dissolved in 5 M sodium hydroxide (4 g, 0.1 mol) solution. After reacting for 30 min, the solution became clear and cooled to 0 °C. Sodium nitrite aqueous solution (8 g, 0.12 mol) was slowly added, and after reacting for 30 min, the reaction solution was slowly added dropwise to sulfuric acid solution (100 mL, 2 M). The reaction was carried out at 0 °C for 30 min. Stannous chloride dihydrate (56 g, 0.25 mol) was dissolved in 40 mL concentrated hydrochloric acid and slowly added dropwise to the reaction solution. After reacting at 0 °C for 2 h, the mixture was filtered, washed with plenty of water, and the solid was collected and dried to obtain compound 3 (12.9 g, yield 78%).

[0029] Step 4) Preparation of compound 5 (1-(4-penten-1-yl)-1 H -Indazole-3-carboxylic acid-D4: Compound 3 (2.5 g, 15 mmol) was dissolved in 16 mL of N,N-dimethylformamide. Sodium tert-butoxide (3.6 g, 38 mmol) was added at 0 °C and reacted for 30 min. Then, 5-bromopentene (2.7 g, 18 mmol) was added, and the reaction was carried out at room temperature for 16 h. Ice water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 5 (3.0 g, 86% yield).

[0030] Step 5) Preparation of compound 6 (N-[[1-(4-penten-1-yl)-1 H [-Indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4: Compound 5 (2.5 g, 10.7 mmol) was dissolved in 25 mL of N,N-dimethylformamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,N-diisopropylethylamine (6.9 g, 53 mmol), and tert-leucine methyl ester hydrochloride (2.9 g, 16 mmol) were added sequentially at 0 °C. After reacting for 30 min, the mixture was allowed to rise to room temperature and reacted for 16 h. Water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 6 (2.9 g, 73% yield). 1 H NMR (600 MHz, DMSO- d 6) δ 7.64 (d, J =9.3 Hz, 1H), 5.82 (ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 5.02 (dq, J = 17.1, 1.7Hz, 1H), 4.98 (dq,J = 10.3, 1.5 Hz, 1H), 4.53-4.49 (m, 3H), 3.70 (s, 3H), 2.07- 2.01 (m, 2H), 1.97 (m, 2H), 1.02 (s, 9H).

[0031] 13 C NMR (150 MHz, DMSO- d 6) δ 171.37, 161.50, 140.63, 137.53, 135.98,126.30, 123.03, 122.51, 121.87, 121.10, 120.06, 115.51, 110.19, 59.38, 51.85,48.20, 34.26, 30.21, 28.47, 26.41.

[0032] Example 2: Compound 8 (N-[[1-(5-fluoropentyl)-1 H Preparation of [-indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4):

[0033] Step 1) Preparation of Compound 1 (2-(hydroxyethylamine)-N-benzene-D4 acetamide): Chloral hydrate (10 g, 0.06 mol) was dissolved in 75 mL of water, and sodium sulfate (50 g, 0.35 mol) was added in portions at 50 °C, stirring until completely dissolved. Aniline-D5 (4.91 g, 0.05 mol) was dissolved in 6 M hydrochloric acid aqueous solution (10 mL) and slowly added dropwise to the mixed solution. Then, hydroxylamine hydrochloride (10.5 g, 0.15 mol) was dissolved in a small amount of water and added dropwise to the reaction solution. The temperature was raised to 80-90 °C and reacted for 2 h. After slow cooling, the mixture was filtered, and the solid was washed with a large amount of water and dried to obtain crude compound 1.

[0034] Step 2) Preparation of compound 2 (indigo-D4): Add 25 mL of concentrated hydrochloric acid to a three-necked flask, heat to 60 °C, add compound 1 to the concentrated hydrochloric acid, keep the temperature below 65 °C, react for 30 min, then heat to 85 °C and react for 15 min, slowly cool to room temperature, slowly pour the reaction solution into ice water, stir for a period of time, a large amount of solid precipitates, filter, wash with ice water, collect the solid and dry to obtain compound 2 (6.0 g, total yield of two steps 79%).

[0035] Step 3) Preparation of compound 3 (indazole-3-carboxylic acid-D4): Compound 2 (15.1 g, 0.1 mol) was dissolved in 5 M sodium hydroxide (4 g, 0.1 mol) solution. After reacting for 30 min, the solution became clear and cooled to 0 °C. Sodium nitrite aqueous solution (8 g, 0.12 mol) was slowly added, and after reacting for 30 min, the reaction solution was slowly added dropwise to sulfuric acid solution (100 mL, 2 M). The reaction was carried out at 0 °C for 30 min. Stannous chloride dihydrate (56 g, 0.25 mol) was dissolved in 40 mL concentrated hydrochloric acid and slowly added dropwise to the reaction solution. After reacting at 0 °C for 2 h, the mixture was filtered, washed with plenty of water, and the solid was collected and dried to obtain compound 3 (12.9 g, yield 78%).

[0036] Step 4) Preparation of compound 7 (1-(5-fluoropentyl)-1 H -Indazole-3-carboxylic acid-D4: Compound 3 (2.5 g, 15 mmol) was dissolved in 16 mL of N,N-dimethylformamide. Sodium hydride (1.5 g, 38 mmol) was added at 0 °C and the reaction was carried out for 30 min. Then, 1-bromo-5-fluoropentane (3.1 g, 18 mmol) was added and the reaction was carried out at room temperature for 16 h. Ice water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The organic phases were combined and purified by column chromatography to give compound 7 (2.9 g, 76% yield).

[0037] Step 5) Preparation of compound 8 (N-[[1-(5-fluoropentyl)-1 H [-Indazole-3-yl]carbonyl]-3-methyl-valine methyl ester-D4: Compound 7 (2.7 g, 10.7 mmol) was dissolved in 25 mL of N,N-dimethylformamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,N-diisopropylethylamine (6.9 g, 53 mmol), and tert-leucine methyl ester hydrochloride (2.9 g, 16 mmol) were added sequentially at 0 °C. After reacting for 30 min, the mixture was allowed to rise to room temperature and reacted for 16 h. Water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 8 (3.2 g, 79% yield). 1 H NMR (600 MHz, DMSO- d 6) δ 7.63 (d, J = 9.3Hz, 1H), 4.54 (t, J = 7.0 Hz, 2H), 4.50 (d, J = 9.3 Hz, 1H), 4.44 (t, J= 6.0Hz, 1H), 4.36 (t, J = 6.0 Hz, 1H), 3.70 (s, 3H), 1.91 (p, J = 7.2 Hz, 2H),1.74-1.62 (m, 2H), 1.36 (p, J = 7.6 Hz, 2H), 1.02 (s, 9H).

[0038] 13 C NMR (150 MHz, DMSO- d 6) δ 171.37, 161.51, 140.65, 135.94, 126.30,122.51, 121.84, 121.10, 110.23, 84.18, 83.11, 59.39, 51.84, 48.58, 34.25,29.33, 29.21, 28.94, 26.40, 22.02, 21.98.

[0039] Example 3: Compound 9 (1-(5-fluoropentyl)-N-(1-methyl-1-phenylethyl)-1 H Preparation of (-indazole-3-carboxamide-D4):

[0040] Step 4) Compound 7 (1-(5-fluoropentyl)-1 H The preparation of (-indazole-3-carboxylic acid-D4) is described in Example 2.

[0041] Step 5) Preparation of compound 9 (1-(5-fluoropentyl)-N-(1-methyl-1-phenylethyl)-1 H -Indazole-3-carboxamide-D4: Compound 7 (2.7 g, 10.7 mmol) was dissolved in 25 mL of N,N-dimethylformamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,N-diisopropylethylamine (2.1 g, 16 mmol), and α,α-dimethylbenzylamine (2.9 g, 16 mmol) were added sequentially at 0 °C and reacted for 30 min. The reaction mixture was then allowed to rise to room temperature and react for 16 h. Water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 9 (3.4 g, 86% yield). 1 H NMR (600 MHz, DMSO- d6) δ 7.97 (s, 1H), 7.46-7.41 (m, 2H), 7.33-7.27 (m, 2H), 7.23-7.16 (m, 1H), 4.52 (t, J = 7.1 Hz, 2H), 4.46 (t, J = 6.0 Hz, 1H), 4.38 (t, J = 6.0 Hz, 1H), 1.93 (p, J = 7.4 Hz, 2H), 1.73 (s, 6H), 1.74-1.68 (m, 1H), 1.68-1.64 (m, 1H), 1.41-1.32 (m, 2H).

[0042] 13 C NMR (150 MHz, DMSO- d 6) δ 161.11, 147.73, 140.56, 137.30, 128.04,125.99, 124.79, 122.06, 121.93, 110.23, 110.01, 84.21, 83.14, 55.15, 48.53,29.53, 29.41, 29.28, 29.07, 22.08, 22.05.

[0043] Example 4: Compound 11 (N-(1-methyl-1-phenylethyl)-(4-cyanobutyl)-1 H Preparation method of (-indazole-3-carboxamide-D4):

[0044] Step 1) Preparation of Compound 1 (2-(hydroxyethylamine)-N-benzene-D4 acetamide): Chloral hydrate (10 g, 0.06 mol) was dissolved in 75 mL of water, and sodium sulfate (50 g, 0.35 mol) was added in portions at 50 °C, stirring until completely dissolved. Aniline-D5 (4.91 g, 0.05 mol) was dissolved in 6 M hydrochloric acid aqueous solution (10 mL) and slowly added dropwise to the mixed solution. Then, hydroxylamine hydrochloride (10.5 g, 0.15 mol) was dissolved in a small amount of water and added dropwise to the reaction solution. The temperature was raised to 80-90 °C and reacted for 2 h. After slow cooling, the mixture was filtered, and the solid was washed with a large amount of water and dried to obtain crude compound 1.

[0045] Step 2) Preparation of compound 2 (indigo-D4): Add 45 mL of trifluoroacetic acid to a three-necked flask, heat to 60 °C, add compound 1 to trifluoroacetic acid, keep the temperature below 65 °C, react for 30 min, then heat to 75 °C and react for 45 min, slowly cool to room temperature, slowly pour the reaction solution into ice water, stir for a period of time, a large amount of solid precipitates, filter, wash with ice water, collect the solid and dry to obtain compound 2 (5.2 g, total yield of two steps 68%).

[0046] Step 3) Preparation of compound 3 (indazole-3-carboxylic acid-D4): Compound 2 (15.1 g, 0.1 mol) was dissolved in 5 M sodium hydroxide (4 g, 0.1 mol) solution. After reacting for 30 min, the solution became clear and cooled to 0 °C. Sodium nitrite aqueous solution (8 g, 0.12 mol) was slowly added, and after reacting for 30 min, the reaction solution was slowly added dropwise to sulfuric acid solution (100 mL, 2 M). The reaction was carried out at 0 °C for 30 min. Stannous chloride dihydrate (56 g, 0.25 mol) was dissolved in 40 mL concentrated hydrochloric acid and slowly added dropwise to the reaction solution. After reacting at 0 °C for 2 h, the mixture was filtered, washed with plenty of water, and the solid was collected and dried to obtain compound 3 (12.9 g, yield 78%).

[0047] Step 4) Preparation of compound 10 (1-(4-cyanobutyl)-1 H -Indazole-3-carboxylic acid-D4: Compound 3 (2.5 g, 15 mmol) was dissolved in 16 mL of N,N-dimethylformamide. Potassium tert-butoxide (4.3 g, 38 mmol) was added at 0 °C and reacted for 30 min. Then, 5-bromopentanilonitrile (2.9 g, 18 mmol) was added, and the reaction was carried out at room temperature for 16 h. Ice water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 7 (2.6 g, 70% yield).

[0048] Step 5) Preparation of compound 11 (N-(1-methyl-1-phenylethyl)-(4-cyanobutyl)-1 H -Indazole-3-carboxamide-D4: Compound 10 (2.6 g, 10.7 mmol) was dissolved in 25 mL of N,N-dimethylformamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,N-diisopropylethylamine (2.1 g, 16 mmol), and α,α-dimethylbenzylamine (2.9 g, 16 mmol) were added sequentially at 0 °C and reacted for 30 min. The reaction mixture was then allowed to rise to room temperature and react for 16 h. Water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 9 (3.2 g, 82% yield).1 H NMR (600 MHz, DMSO- d 6) δ 7.99 (s, 1H), 7.46-7.42 (m, 2H), 7.32-7.28 (m, 2H), 7.22-7.17 (m, 1H), 4.55 (t, J = 7.1 Hz, 2H), 2.57 (t, J = 7.1 Hz, 2H), 2.01-1.95 (m, 2H), 1.73 (s, 6H), 1.62-1.55 (m, 2H).

[0049] 13 C NMR (150 MHz, DMSO- d 6) δ 161.07, 147.71, 140.58, 137.47, 128.04,126.18, 125.98, 124.79, 122.14, 121.94, 120.57, 110.18, 109.94, 55.17, 47.81,29.53, 28.50, 22.20, 15.81.

[0050] Example 5: Compound 13 (2-[1-(4-fluorobutyl)-1) H Preparation of methyl 3,3-dimethylbutyrate (D4) of [-indazole-3-formylamino]-3,3-dimethylbutyrate:

[0051] Step 3) Preparation of compound 3 (indazole-3-carboxylic acid-D4) refers to Example 1.

[0052] Step 4) Preparation of compound 12 (1-(4-fluorobutyl)-1 H -Indazole-3-carboxylic acid-D4: Compound 3 (2.5 g, 15 mmol) was dissolved in 16 mL of N,N-dimethylformamide, and reacted for 30 min at 0 °C with 38 mL (38 mmol) of 1 M bis(trimethylsilylamino)lithium tetrahydrofuran solution. Then, 1-bromo-4-fluorobutane (2.8 g, 18 mmol) was added, and the reaction was carried out at room temperature for 16 h. Ice water was added to the reaction solution, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 12 (2.4 g, 67% yield).

[0053] Step 5) Preparation of compound 13 (2-[1-(4-fluorobutyl)-1 H[-Indazole-3-formylamino]-3,3-dimethylbutyrate methyl ester-D4: Compound 12 (2.6 g, 10.7 mmol) was dissolved in 25 mL of N,N-dimethylformamide. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16 mmol), 1-hydroxybenzotriazole (2.2 g, 16 mmol), N,N-diisopropylethylamine (6.9 g, 53 mmol), and tert-leucine methyl ester hydrochloride (2.9 g, 16 mmol) were added sequentially at 0 °C. After reacting for 30 min, the mixture was allowed to rise to room temperature and reacted for 16 h. Water was added to the reaction mixture, and the mixture was extracted multiple times with ethyl acetate. The combined organic phases were purified by column chromatography to give compound 13 (3.5 g, 89% yield).

[0054] 1 H NMR (600 MHz, DMSO- d 6) δ 7.65 (d, J = 9.2 Hz, 1H), 4.57 (t, J = 7.1Hz, 2H), 4.53-4.47 (m, 2H), 4.43 (t, J = 6.0 Hz, 1H), 3.70 (s, 3H), 2.00-1.93 (m, 2H), 1.71-1.60 (m, 2H), 1.02 (s, 9H).

[0055] 13 C NMR (150 MHz, DMSO- d 6) δ 171.38, 161.51, 140.66, 136.08, 126.37,122.54, 122.28, 121.86, 121.12, 83.90, 82.83, 59.41, 51.85, 48.33, 34.27,27.19, 27.06, 26.42, 25.41, 25.37.

[0056] The beneficial effects of the above technical solution are as follows: The raw materials are cheap and readily available, lowering the cost threshold: Aniline-D5 is used as the starting material (replacing the "difficult-to-obtain D6-indazole" in the background technology). Aniline-D5 is a common deuterated reagent in the chemical industry (easy to purchase on the market, and the price is only 1 / 3 to 1 / 2 of D6-indazole). In addition, chloral hydrate, hydroxylamine hydrochloride, sodium sulfate and other materials are all common chemical raw materials (low purchase cost and stable supply). This solves the pain point of "difficult-to-obtain raw materials" from the source, reducing the cost of raw materials per batch.

[0057] The process is green and safe, avoiding high-risk reagents: No highly toxic gases (such as carbon monoxide) are used throughout the process: Step 3 adopts a series process of "ring opening-diazotization-reduction-cyclization" to replace the "carbon monoxide carbonyl insertion reaction" in the background technology, eliminating the risk of highly toxic raw materials; at the same time, the acid reaction in Step 2 and the alkaline conditions in Step 4 are mild reaction environments (no need for high temperature and high pressure), and the amount of waste gas / waste liquid generated is reduced compared with the traditional route, which is in line with "green chemical industry".

[0058] This invention uses aniline-D5 as a raw material, and through a multi-step reaction, obtains the key intermediate indazole-3-carboxylic acid-D4. This intermediate is first alkylated with a haloalkane, and then undergoes an amide condensation reaction with an amine compound to obtain a deuterated internal standard for indazole synthetic cannabinoids. The raw materials used in this invention are inexpensive and readily available, and the preparation method is simple, thus achieving the goal of green and safe preparation of deuterated internal standards for indazole synthetic cannabinoids, providing strong support for forensic identification and drug control work.

[0059] Example 6: Before the batch of raw materials in step 1 of the current batch is processed, step 01 is performed. Step 01 includes: Step 011: Determine the key raw material parameters of the raw materials in the current batch of Step 1 based on the detection. The key raw material parameters include: the crystallinity coefficient of aniline-D5. Step 012: Obtain the reference reaction temperature range for each reaction stage under the raw material composition conditions of the current batch Step 1, and the fitting curve of the first reaction temperature - reference equilibrium constant for each reaction stage under the same raw material composition conditions of the current batch Step 1; the first reaction temperature is selected from the corresponding reference reaction temperature range according to the preset temperature gradient; Step 1 is divided into 2 reaction stages: induction reaction stage and main reaction stage; Step 013: Obtain the benchmark key reaction parameters corresponding to each first reaction temperature. The benchmark key reaction parameters include: the benchmark resistance fluctuation coefficient and the benchmark reaction rate coefficient for each reaction stage. Step 014: Based on steps 012 and 013, select the target first reaction temperature for each reaction stage; Step 015: Based on the crystallinity coefficient of aniline-D5 obtained in Step 011, the target first reaction temperature for each reaction stage is corrected to obtain the second reaction temperature for each reaction stage; Step 016: Conduct reaction tests at the second reaction temperature of each reaction stage, and determine the actual resistance fluctuation coefficient and actual reaction rate coefficient, the actual equilibrium constant when the reaction reaches equilibrium, and the side reaction inhibition coefficient for each reaction stage; Step 017: Based on step 016, correct the second reaction temperature of each reaction stage to obtain the target reaction temperature of each reaction stage.

[0060] Crystallinity coefficient of aniline-D5: The crystal structure of the raw material is detected by XRD diffraction, and the crystallinity coefficient is obtained by calculating "crystallization peak area / total peak area" (e.g., area ratio 0.8 → crystallinity coefficient 0.8).

[0061] The "key characteristics" of the raw material composition (including chemical characteristics, physical characteristics, and proportioning characteristics) are encoded as digital tags. In the enterprise database, the mapping relationship between "characteristic tag → baseline reaction conditions (including baseline reaction temperature and the stirring rate corresponding to the baseline reaction temperature)" is pre-stored. The system uses SQL queries to match historical batches or experimental batches in the database that have "identical / similar characteristic tags" and whose reactions have passed. The baseline reaction conditions are determined as follows: For the same raw material composition, reaction experiments are conducted, the reaction effects are monitored, and combinations that meet multiple reaction effect indicators (temperature, stirring) are screened. These are then verified through pilot-scale testing to determine the initial baseline reaction conditions for each reaction stage. During actual historical production, the initial baseline reaction conditions are dynamically updated and adjusted, and the database retains the latest baseline reaction conditions. If three consecutive batches show abnormal reaction indicators, a dynamic update is triggered, calling up data from multiple batches and using an algorithm to refit the mapping relationship, generating and retaining the latest baseline conditions to ensure production adapts to raw material fluctuations. For each reaction stage, a separate "temperature gradient experiment" is performed (e.g., 40-60℃ for the induction stage and 70-90℃ for the main reaction stage). The equilibrium constants at different temperatures (when the reaction stage is completed) are measured, and the fitting curve of the first reaction temperature-reference equilibrium constant for each reaction stage is obtained.

[0062] The equilibrium constant is the ratio of the product of the product concentrations raised to their powers to the product of the reactant concentrations raised to their powers. Resistance fluctuation coefficient: The system resistance is measured using an online viscometer, and calculated as "(real-time resistance - reference resistance) / reference resistance value". The above resistance is determined based on the conversion between viscosity and resistance. Reaction rate coefficient: Measure the change in raw material concentration using an online infrared spectrometer and calculate "concentration change / time" (e.g., concentration changes from 1 mol / L to 0.5 mol / L within 10 min → reaction rate coefficient = 0.05 min⁻¹).

[0063] From the first reaction temperature, select the first reaction temperature of each reaction stage that meets the criteria such as "small fluctuations and the required reaction rate coefficient for each raw material reaction stage" as the target first reaction temperature for each stage.

[0064] ; in, This is the second reaction temperature of the current reaction stage; The target first reaction temperature for the current reaction stage; The crystallinity coefficient of aniline-D5 obtained in step 011; The crystallinity coefficient of the baseline aniline-D5 (the crystallinity coefficient determined by the "standard stable batch" aniline-D5 feedstock, representing the "ideal feedstock state" during process validation, and serving as a "reference baseline" for temperature compensation); The crystallinity coefficient of aniline-D5 at the current reaction stage is calculated as the reaction temperature compensation coefficient (calibrated through a "crystallization gradient experiment": keeping other conditions constant, changing the crystallinity of aniline-D5, determining the temperature compensation amount required to "achieve the desired reaction parameters," and then fitting the result). ); The side reaction inhibition coefficient is: the maximum value of the first ratio (byproduct concentration / target product concentration) corresponding to all byproducts; ; in, The target reaction temperature for the current reaction stage; These are the deviations of the actual resistance fluctuation coefficient of the current reaction stage (actual resistance fluctuation coefficient - corresponding benchmark resistance fluctuation coefficient), the deviation of the actual reaction rate coefficient of the current reaction stage (actual reaction rate coefficient - corresponding benchmark reaction rate coefficient), and the deviation of the actual equilibrium constant of the current reaction stage when the reaction reaches equilibrium (actual equilibrium constant when the reaction reaches equilibrium - benchmark equilibrium constant corresponding to the curve of the second reaction temperature of the current reaction stage at the corresponding first reaction temperature - benchmark equilibrium constant fitting curve). This represents the side reaction inhibition coefficient corresponding to the current reaction stage. These are the parameters for correcting resistance fluctuations, reaction rate coefficients, equilibrium constants, and side reaction inhibition (all in °C; obtained by measuring temperature changes while keeping other conditions constant in the experiment). The beneficial effects of the above technical solution are as follows: Step 011 involves detecting the crystallinity coefficient of aniline-D5. Subsequent steps use this coefficient to adjust the temperature accordingly, allowing the reaction system to automatically adapt to raw materials with different crystallinity levels. For example, when the raw material has high crystallinity (regular molecular arrangement, low reactivity), the system will increase the temperature to ensure the reaction proceeds at the expected rate and extent. This avoids situations where some batches react quickly while others react slowly due to large differences in raw material crystallinity, leading to inconsistent product quality and production schedules. This ensures more consistent initial reaction conditions when different batches of raw materials participate in the reaction.

[0065] Steps 012-014: Setting Temperatures and Baseline Parameters for Different Reaction Stages: Based on the reaction mechanisms of different reaction stages, such as the induction reaction and the main reaction, determine appropriate temperature ranges and baseline parameters (e.g., baseline resistance fluctuation coefficient, baseline reaction rate coefficient). The induction reaction stage focuses on the initial reactions, such as the activation of raw materials. By setting the temperature appropriately, the raw materials can smoothly complete the initial conversion in this stage. The main reaction stage focuses on the efficient generation of the target product. Precise temperature control can promote the reaction towards generating more target products, avoiding problems such as excessively high temperatures in the induction reaction stage prematurely leading to an increase in by-products in the main reaction, or insufficient temperatures in the main reaction stage causing incomplete reactions, all within a broad and uniform temperature range. This ensures that each reaction stage can proceed in an environment more suited to its own characteristics.

[0066] Steps 013-014: Calibrate the baseline parameters: Clarify the resistance fluctuations, reaction rates, and other conditions under the ideal conditions for each reaction stage. In subsequent actual reactions, the actual parameters can be compared with these parameters to provide a clear and referable standard for judging whether the reaction is proceeding normally. Deviations of actual parameters from the baseline can be detected and adjusted in a timely manner.

[0067] When the actual crystallinity of the raw materials differs from the reference crystallinity, adjusting the temperature effectively compensates for the impact of this change in crystallinity on the reaction. Steps 016-017 further refine the temperature based on actual reaction parameters: through actual reaction testing, the actual resistance fluctuation coefficient, actual reaction rate coefficient, actual equilibrium constant, and side reaction inhibition coefficient are obtained. These parameters are then compared with the reference parameters to further refine the temperature and obtain the target reaction temperature. This ensures that the reaction temperature not only considers the initial characteristics of the raw materials but also allows for timely adjustment based on changes occurring during the actual reaction process (such as abnormally increased resistance, slower reaction rate, and increased side reactions), ensuring that the reaction always proceeds under conditions more conducive to the formation of the target product, suppression of side reactions, and maintenance of a suitable reaction rate and system stability.

[0068] Through the above series of temperature design and modification processes, the overall reaction effect can achieve the following results: higher yield and better purity of the target product, smaller quality differences between different batches of products, more stable and controllable reaction cycle, effective suppression of by-product formation, more efficient use of raw materials and energy, and reduced risk of equipment wear and production interruption due to reaction abnormalities. This allows the entire production process, from raw material input to product output, to reach a new level in terms of quality, efficiency, and stability, thereby improving the reliability and economy of production.

[0069] Example 7: The reaction process in step 2 is divided into several consecutive reaction periods, each corresponding to a baseline reaction temperature range; during batch reaction, each reaction period reacts at the corresponding target temperature. Step 02 is performed before batch step 2 using the current batch of acid. Step 02 includes: Step 021 also obtains: baseline data for the initial reaction period of the same acid in the current batch with Compound 1: the fitted curve of the initial reaction temperature versus the baseline conversion rate of Compound 1, the baseline isothermal value, and the target temperature difference range for the next reaction period; it also includes the initial reaction period's... The corresponding baseline value; Step 022: Sample the current batch of acid and compound 1 and conduct an initial reaction with the initial reaction period controlled by the baseline isothermal value. Perform multiple pH and temperature measurements to determine the actual carbon-deuterium bond retention state and the actual acid-deuterium perturbation state. Step 022 includes: Step 022a: In the preliminary experiment, add the current batch of acid and compound 1 according to the settings, inject them into the reaction vessel; use the initial reaction temperature as the reference constant temperature value of the initial reaction period, and stir with a stirring device (the reference stirring speed can be used); Step 022b: A distributed pH sensor array installed on the inner wall of the reaction vessel synchronously collects pH values ​​from different areas; Step 022c: The control unit compares the pH change curve from step 022b with the reference pH change curve and determines the actual carbon-deuterium bond retention state value by the difference in curve slope. Step 022d: Based on the real-time pH data from step 022b, determine the actual acid-deuterium perturbation state value based on the pH fluctuation amplitude; Step 024: Determine the temperature inertia coefficient of the previous reaction period; Step 025: Determine the target temperature of the next reaction period based on the temperature inertia coefficient of the previous reaction period, the median of the target temperature difference range between the previous and next reaction periods, the inter-period temperature fluctuation coefficient between the previous and next reaction periods, and the target temperature of the previous reaction period. Repeat steps 024-025 until the target temperature for all reaction periods has been determined.

[0070] Specifically, obtaining baseline data on the reaction of the same acid with compound 1 at different reaction stages in the current batch of acid includes: Standard / benchmark experimental design: Material and equipment preparation: Materials: Select acid of the same type, specification, and historically stable batch as the "current batch acid" (e.g., all are sulfuric acid of fixed concentration); use the standard specified in the process for compound 1.

[0071] Equipment: Uses reaction vessels consistent with production; equipped with standard sensor sets: distributed pH electrodes (3-point arrangement), Pt100 temperature sensor, and stirring device (such as magnetic stirrer).

[0072] Experimental conditions set (simulating a "standard production environment"): Temperature control: The initial reaction period reference constant temperature value is set as the reference value, and the temperature is precisely controlled by the jacket circulating water (fluctuation ≤ ±0.5℃). Material proportioning: Add according to the standard proportions of the production process; Stirring strategy: Use a reference speed to avoid interference caused by differences in stirring.

[0073] The baseline isothermal value is determined through multiple rounds of experiments, aiming to achieve a suitable reaction rate, high product selectivity, and stable carbon-deuterium bond retention. Experiments are conducted at several selected temperatures to measure conversion rate, product selectivity, and carbon-deuterium bond retention. Data modeling is then used to find the optimal range. Finally, stable batch verification on production equipment is performed to determine the temperature that consistently meets the reaction requirements, which serves as the baseline isothermal value. This value can be dynamically updated based on historical batches that have passed reaction testing.

[0074] Experimental conditions for different reaction periods (simulating a "standard production environment"): For different reaction periods (such as the initial reaction period), experimental conditions related to various baseline parameters are set separately: Temperature-dependent: The baseline constant temperature value for each reaction period is set to the baseline value for the corresponding reaction period. The temperature is precisely controlled by the jacket circulating water, and the temperature fluctuation is ≤ ±0.5℃.

[0075] The baseline isothermal values ​​for each reaction period were determined through multiple rounds of experiments: several temperatures were selected for each reaction period, and the conversion rate, product selectivity, carbon-deuterium bond retention, etc., were measured within that reaction period. The optimal temperature range was found by combining data modeling, and then verified by stable batches in production equipment to determine the temperature that can stably meet the reaction requirements as the baseline value, which can be dynamically updated based on qualified historical batches.

[0076] The target temperature difference range between the previous reaction period and the next reaction period: By statistically analyzing the temperature data of the previous reaction period and the next reaction period in multiple normal production batches, and combining the thermodynamic and kinetic laws of the reaction, the temperature difference range that can ensure a smooth transition of the reaction and stable product quality is determined as the benchmark for the target temperature difference range.

[0077] Reference speed: Experiments were conducted at different speeds using pH sensors distributed at different locations in the reactor to measure pH fluctuations at different speeds. The standard deviation of the fluctuations was calculated, and the speed that minimized pH fluctuations (meeting production requirements) and reduced energy consumption was selected. Production verification confirmed that the speed that ensured a uniform reaction system and energy efficiency was adopted as the reference speed.

[0078] The baseline equilibrium pH is the reference pH value at which the reaction reaches equilibrium, determined through extensive experiments or theoretical calculations. The average pH of the baseline pH curve is calculated from the data of the corresponding time period of the baseline pH curve. The baseline data management system organizes various baseline data (temperature, pH, resistance, reaction rate, etc.) for different reaction periods into structured files; the control system can retrieve baseline data in real time according to the reaction period through a database interface (such as SQL query) for comparative calculation of "preliminary experiments of the current batch of acid in the corresponding reaction period".

[0079] Statistical analysis was performed on standard experimental data from multiple initial reaction periods. The difference between the maximum and minimum pH values ​​in each experimental group was calculated. The average of these differences or a typical value was determined through statistical analysis and used as the benchmark value.

[0080] The horizontal axis of the pH change curve represents the reaction time, and the vertical axis represents the average pH corresponding to the reaction time. Among them, the actual carbon-deuterium bond retention state value is used to quantify the stability of the carbon-deuterium bond during the reaction process;

[0081] Where R is the actual carbon-deuterium bond retention state value; The characteristic slope of the baseline pH curve during the initial reaction period; The characteristic slope of the actual pH curve during the initial reaction period; The average pH of the baseline pH curve during the initial reaction period; The average pH of the actual pH curve during the initial reaction period; The baseline equilibrium pH for the initial reaction period; The characteristic slope is as follows: the subsequence of the active reaction period of the initial reaction period is extracted (e.g., the first 2 minutes of the uneven mixing stage are removed, and the data from the 3rd to the 15th minute are taken); based on these filtered data, the linear least squares method is used to perform overall fitting calculation to fit an optimal straight line, and the equation of the straight line is pH(t) = k・t + b (where t is time, pH(t) is the pH value at the corresponding time, and b is the intercept), and the slope k in the equation is the characteristic slope; Actual acid-deuterium perturbation state values: ; Where U is the actual acid-deuterium perturbation state value; The standard deviation of pH for the actual reaction during the initial reaction period (first, obtain the average value of all pH sensor readings at a single reaction time, and then determine the standard deviation of the average value corresponding to multiple reaction times). This represents the difference between the maximum and minimum pH values ​​of the actual reaction during the initial reaction period. For the initial reaction period and The corresponding baseline value; Step 023: Based on the actual carbon-deuterium bond retention state value, the actual acid-deuterium perturbation state value, and the initial reaction temperature-compound 1 baseline conversion fitting curve, the initial reaction period baseline isothermal value is corrected to obtain the target temperature for the initial reaction period; specifically: ; in, The target temperature for the initial reaction period; This is the baseline isothermal value for the initial reaction period; The ideal acid-deuterium perturbation state value ("U with the highest conversion rate in the preliminary experiment") is taken as... ); These are the corrected weighting coefficients for the actual carbon-deuterium bond retention states (amplifying / reducing the effect of carbon-deuterium bond retention on temperature, with values ​​of 0.1-0.5; positively correlated with the reaction's sensitivity to carbon-deuterium bonds), the corrected weighting coefficients for the actual acid-deuterium perturbation states (amplifying / reducing the effect of acid-deuterium perturbation on temperature, with values ​​of 0.2-0.6; positively correlated with the reaction's sensitivity to acid perturbation), and the corrected weighting coefficients for the conversion rate (with values ​​of 0.3-0.8, positively correlated with the conversion rate's sensitivity to temperature). This is a conversion rate correction factor; ; in, The target conversion rate for the initial reaction period (conversion rate at the end of the initial reaction period). The actual conversion rate during the initial reaction period (the actual conversion rate at the end of the initial reaction period), where e is the natural constant. The first slope represents the initial reaction period, and the temperature-compound 1 baseline conversion fitting curve represents the reaction temperature. The average slope within the region; The second slope represents the initial reaction period in the temperature-compound 1 baseline conversion fitting curve. The average slope within the region; This is a correction factor (the correction factor amplifies the effect of the slope, and is usually taken as 1-3 (to balance the steepness of the Sigmoid curve). Values ; Design a three-factor, five-level orthogonal experiment (with five gradients each for carbon-deuterium bond retention R, perturbation U, and conversion rate X), and record the corresponding optimal temperature adjustment amount; use the least squares method to fit the experimental data and obtain the weight coefficients of each factor on the temperature correction.

[0082] With other parameters fixed, test in a small-scale trial. Temperature correction effect when =1, 2, 3); select the option corresponding to "Conversion rate meets target and fluctuation ≤3%". Values ​​(higher values ​​for sensitive reactions, lower values ​​for stable reactions).

[0083] Step 024: Determine the temperature inertia coefficient of the previous reaction period, specifically: ; in, The temperature inertia coefficient for the i-th (greater than or equal to 1) reaction period; The target temperature for the i-th reaction period; The maximum allowable temperature difference for the reaction process during the i-th reaction period; Step 025: Determine the target temperature of the next reaction period based on the temperature inertia coefficient of the previous reaction period, the median of the target temperature difference range between the previous and next reaction periods, the inter-period temperature fluctuation coefficient between the previous and next reaction periods, and the target temperature of the previous reaction period. ; in, The target temperature for the (i+1)th reaction period; The median value of the target temperature difference between the i-th reaction period and the (i+1)-th reaction period; Let be the actual temperature standard deviation of the reaction process during the i-th reaction period; The allowable standard deviation of temperature for the reaction process in the (i+1)th reaction period; These represent the temperature compensation amount corresponding to the unit temperature inertia coefficient and the state of temperature difference, respectively. Corresponding temperature compensation amount, unit intertemporal temperature fluctuation coefficient The corresponding temperature compensation amount (in °C). Let be the inter-period temperature fluctuation coefficient between the i-th reaction period and the (i+1)-th reaction period; i is greater than or equal to 2; The target temperature difference between the previous reaction period and the next reaction period is a key constraint that needs to be considered in the process (it is necessary to ensure that the reaction transitions smoothly within a reasonable temperature range).

[0084] Chemical reaction systems exhibit thermal inertia (e.g., the heat capacity of the reaction vessel and materials causes a lag in temperature changes). The temperature state of the previous reaction period will have an "inertial" influence on the temperature control of the next reaction period.

[0085] The calibration was performed using a combination of "controlled variables + orthogonal experiments + regression fitting". The beneficial effects of the above technical solution are as follows: For the current batch of raw materials (such as acid concentration and impurity composition), the reaction temperature is dynamically adjusted by detecting data such as pH changes and carbon-deuterium bond retention status through preliminary experiments. Compared with fixed process parameters, this ensures that key product quality indicators (such as carbon-deuterium bond retention rate) and conversion rate meet requirements due to differences in raw materials.

[0086] Intercepting abnormal batches in advance: Before mass production, by comparing the baseline pH change curve and temperature curve through pre-experiments, and using indicators such as the difference in curve slope and pH fluctuation amplitude, problems such as abnormal carbon-deuterium bond retention and excessive acid-deuterium disturbance can be identified in advance. Early warnings and adjustments can be made in the early stages of production to avoid scrapping the entire batch of materials and reduce losses from abnormal batches.

[0087] Shorten the mass production debugging cycle: Preliminary experiments have verified the multi-reaction period temperature iteration logic (such as the adaptability of coefficients for inertia compensation and temperature difference correction), so there is no need to repeatedly explore process parameters during mass production.

[0088] By integrating the temperature inertia coefficient, the median inter-period temperature difference, and the inter-period temperature fluctuation coefficient, a three-dimensional quality correction model of "inertia-temperature difference-fluctuation" is constructed. The temperature is iteratively corrected at each step of the reaction to continuously offset the cumulative effects of temperature lag and fluctuation during the reaction process, ensuring that the pass rate of key product quality indicators (such as deuteration sites and isomer purity) is increased to over 98% in complex continuous reactions (such as multi-step deuteration synthesis).

[0089] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A method for preparing an indazole-based synthetic cannabinoid deuterated internal standard, characterized in that: include: Step 1: Aniline-D5 reacts with chloral hydrate and hydroxylamine hydrochloride in an aqueous sodium sulfate solution to generate compound 1; Step 2: Compound 1 is reacted with acid to form compound 2; Step 3: Compound 2 undergoes ring-opening, diazotization, reduction, and cyclization to form compound 3; Step 4: Compound 3 reacts with a haloalkane under alkaline conditions to generate compound 4; Step 5: Compound 4 undergoes an amide condensation reaction with an amine compound to obtain an indazole-based deuterated internal standard for synthetic cannabinoids.

2. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The structural formula of the deuterated internal standard of indazole synthetic cannabinoids is as follows: 。 3. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The R1 in the structural formula of the indazole synthetic cannabinoid deuterated internal standard is any of the following: 。 4. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The R2 in the structural formula of the indazole synthetic cannabinoid deuterated internal standard is any of the following: 。 5. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The synthetic route includes steps 1 through 5: 。 6. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The acid in step 2 includes any one of concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, trifluoroacetic acid, acetic acid, propionic acid, and butyric acid.

7. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The alkali in step 4 includes any one of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen, butyllithium, lithium bis(trimethylsilylamino)amine, sodium bis(trimethylsilylamino)amine, and potassium bis(trimethylsilylamino)amine.

8. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: Before the current batch of raw materials for step 1 is processed, step 01 is performed. Step 01 includes: Step 011: Determine the key raw material parameters of the raw materials in the current batch of Step 1 based on the detection. The key raw material parameters include: the crystallinity coefficient of aniline-D5. Step 012: Obtain the baseline reaction temperature range for each reaction stage under the raw material composition conditions of the current batch Step 1, and the fitting curve of the first reaction temperature - baseline equilibrium constant for each reaction stage under the same raw material composition conditions of the current batch Step 1; the first reaction temperature is selected from the corresponding baseline reaction temperature range according to the preset temperature gradient. Step 013: Obtain the benchmark key reaction parameters corresponding to each first reaction temperature. The benchmark key reaction parameters include: the benchmark resistance fluctuation coefficient and the benchmark reaction rate coefficient for each reaction stage. Step 014: Based on steps 012 and 013, select the target first reaction temperature for each reaction stage; Step 015: Based on the crystallinity coefficient of aniline-D5 obtained in Step 011, the target first reaction temperature for each reaction stage is corrected to obtain the second reaction temperature for each reaction stage; Step 016: Conduct reaction tests at the second reaction temperature of each reaction stage, and determine the actual resistance fluctuation coefficient and actual reaction rate coefficient, the actual equilibrium constant when the reaction reaches equilibrium, and the side reaction inhibition coefficient for each reaction stage; Step 017: Based on Step 016, correct the second reaction temperature of each reaction stage to obtain the target reaction temperature of each reaction stage; Step 1 is divided into two reaction stages: the induction reaction stage and the main reaction stage.

9. The method for preparing an indazole-based synthetic cannabinoid deuterated internal standard according to claim 1, characterized in that: The reaction process in step 2 is divided into several consecutive reaction periods, each with a corresponding baseline reaction temperature range; during batch reaction, each reaction period is carried out at the corresponding target temperature. Before performing batch step 2 using the current batch of acid, step 02 is performed. Step 02 includes: Step 021 also obtains: baseline data on the initial reaction period of the current batch of acid with compound 1; Step 022: Sample the current batch of acid and compound 1 and conduct an initial reaction with the initial reaction period controlled by the baseline isothermal value. Perform multiple pH and temperature measurements to determine the actual carbon-deuterium bond retention state and the actual acid-deuterium perturbation state. Step 023: Based on the actual carbon-deuterium bond retention state value, the actual acid-deuterium perturbation state value, and the initial reaction temperature-compound 1 baseline conversion fitting curve, the baseline isothermal value of the initial reaction period is corrected to obtain the target temperature of the initial reaction period; Step 024: Determine the temperature inertia coefficient of the previous reaction period; Step 025: Determine the target temperature of the next reaction period based on the temperature inertia coefficient of the previous reaction period, the median of the target temperature difference range between the previous and next reaction periods, the inter-period temperature fluctuation coefficient between the previous and next reaction periods, and the target temperature of the previous reaction period. Repeat steps 024-025 until the target temperature for all reaction periods has been determined.

10. The method for preparing a deuterated internal standard of indazole synthetic cannabinoids according to claim 9, characterized in that: Step 021 also obtains: the baseline data for the initial reaction period of the same acid in the current batch with compound 1: the fitted curve of the reaction temperature-baseline conversion rate of compound 1 during the initial reaction period, the baseline isothermal value, and the range of target temperature difference values ​​with the next reaction period; Step 022 includes: Step 022a: In the preliminary experiment, add the current batch of acid and compound 1 according to the settings, inject them into the reaction vessel; use the initial reaction temperature as the reference constant temperature value of the initial reaction period, and stir with a stirring device; Step 022b: A distributed pH sensor array installed on the inner wall of the reaction vessel synchronously collects pH values ​​from different areas; Step 022c: The control unit compares the pH change curve from step 022b with the reference pH change curve and determines the actual carbon-deuterium bond retention state value by the difference in curve slope. Step 022d: Based on the real-time pH data from step 022b, determine the actual acid-deuterium perturbation state value based on the pH fluctuation amplitude.

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