Synthesis method of deuterated tetrabenazine

Abstract

The invention relates to the technical field of medicine synthesis, and discloses a synthetic method of deuterated tetrabenazine. The synthesis method of the deuterated tetrabenazine comprises the following steps: taking 6, 7-bis (methoxy-d3)-3, 4-dihydroisoquinoline hydrochloride (1: 1) and 3-(bromomethyl)-5-methylhexane-2-ketone as raw materials, carrying out addition elimination reaction in a solvent, and carrying out proper post-treatment to obtain the deuterated tetrabenazine. The method has the advantages that the raw materials are easy to obtain, the cost is low, the reaction is environment-friendly, the reaction is easy to control and the like, meanwhile, the yield of the deuterated tetrabenazine is increased, the post-treatment is simple, the product is easy to purify, and the production cost of the deuterated tetrabenazine is further reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, in particular to a method for synthesizing deuterated tetrabenazine. Background Art

[0002] Deutetrabenazine is a chemical. Its chemical name is cis-9,10-(dimethoxy-D6)-1,3,4,6,7,11β-hexahydro-3-isobutyl-2H-benzo[α]quinolizin-2-one, and its molecular formula is C 19 H 25 D2NO3 is a drug used to treat tardive dyskinesia and chorea associated with Huntington's disease. Tetrabenazine was first launched in Switzerland for the treatment of schizophrenia and was approved by the US FDA in 2008 for the treatment of Huntington's disease. Deuterated tetrabenazine was launched in the United States in 2017 and subsequently approved in China. It produces pharmacological activity by reversibly inhibiting the monoamine transporter 2 (VMAT2) in the central nervous system to reduce the supply of monoamine compounds. Deuterated tetrabenazine is a safe and effective drug for the treatment of various hyperkinetic disorders. Compared with traditional antipsychotics, deuterated tetrabenazine does not cause tardive dyskinesia.

[0003] However, most of the preparation methods of deuterated tetrabenazine reported in the literature have problems such as many steps, long cycles, large solvent usage, use of hazardous materials, severe equipment corrosion, high risk factors, waste gas generation, and high equipment requirements, which are not in line with modern safe, green, and environmentally friendly production concepts. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing deuterated tetrabenazine. The method uses 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) and 3-(bromomethyl)-5-methylhexane-2-one as raw materials, undergoes an addition-elimination reaction in a solvent, and undergoes post-treatment to obtain deuterated tetrabenazine. This synthesis method is low-cost, requires only a few reaction steps, has a high yield, and is suitable for industrial production.

[0005] The technical solution adopted by the present invention to solve its technical problem is:

[0006] A method for synthesizing deuterated tetrabenazine specifically comprises the following steps:

[0007] Step S1, addition elimination reaction: adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride and 3-(bromomethyl)-5-methylhexane-2-one to a first solvent, and causing an addition elimination reaction under base catalysis to obtain a finished reactant system;

[0008] Step S2, post-treatment: adding water to the finished product reaction system obtained in step S1, cooling and crystallizing, filtering, washing with water, draining, and drying to obtain a crude deuterated tetrabenazine;

[0009] Step S3, refining: the crude deuterated tetrabenazine obtained in step S2 is mixed with a refining solvent and refined to obtain a refined system; the refined system is crystallized and filtered in sequence to obtain a filter cake; the filter cake is washed and dried in sequence to obtain a finished deuterated tetrabenazine.

[0010] In step S1, a deuterated raw material (6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride) is reacted with 3-(bromomethyl)-5-methylhexane-2-one to directly introduce deuterium atoms, thereby avoiding the complexity and side reactions of the subsequent deuteration step and improving the purity and yield of the deuterated product. In step S2, unreacted raw materials, inorganic salts and other impurities are effectively removed through water crystallization and washing, thereby simplifying the purification process. In step S3, the product is further purified through solvent refining and low-temperature crystallization to ensure that the chemical purity and deuteration rate of deuterated tetrabenazine meet pharmaceutical standards.

[0011] Furthermore, in step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline and hydrochloric acid in 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride is 1:1, which can ensure that the raw materials participate in the reaction in the form of a stable hydrochloride, avoid side reactions caused by free base, and improve the controllability and reproducibility of the reaction.

[0012] Furthermore, in step S1, the first solvent is selected from one or more of ethanol (EtOH), isopropanol (i-PrOH), methanol (MeOH), and water, which is beneficial to dissolving the raw materials and promoting the reaction; the mass ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to the first solvent is 1:(4 to 10), which can balance the reaction concentration and efficiency, and avoid post-processing difficulties or reduced yields due to excessive first solvent.

[0013] Furthermore, in step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to 3-(bromomethyl)-5-methylhexane-2-one is 1:(1.2-1.5). This optimizes the raw material ratio. This helps to improve the reaction conversion rate and product yield, avoids raw material waste, and reduces production costs.

[0014] Furthermore, in step S1, the base catalyst is selected from one or more of potassium carbonate (K2CO3), N,N-diisopropylethylamine (DIPEA), potassium bicarbonate (KHCO3), and sodium hydroxide (NaOH). The base catalyst promotes efficient reaction, improves the selectivity and yield of the reaction, and helps to obtain a high-purity target product.

[0015] Furthermore, in step S1, the reaction temperature of the addition-elimination reaction is 30-50° C., and the reaction time is 16-48 hours. The addition-elimination reaction is completed under mild conditions, reducing side reactions (such as over-alkylation or deuterated site exchange) and ensuring product stability.

[0016] Furthermore, in step S3, the refining solvent is selected from one or more of ethanol, methanol, and water; and the mass ratio of the crude deuterated tetrabenazine to the refining solvent is 1:(3-8). The use of the above refining solvent system is beneficial to the purification of the product and the improvement of the yield, helps to remove impurities, and obtains a high-purity target product.

[0017] Furthermore, in step S3, the refining temperature is 50° to 80°C and the refining time is 0.5 to 2 hours. The refining conditions are optimized to ensure that the deuterated product is completely dissolved while avoiding high temperature degradation, shortening the process cycle and ensuring the purity and stability of the product.

[0018] Furthermore, in step S3, the crystallization temperature is 0-5° C. This crystallization temperature can improve the product yield and reduce solvent residue, which helps to obtain the target product with uniform particles and high purity, and meets the crystal form control requirements of the raw material.

[0019] Furthermore, in step S3, the filter cake washing solvent is ethanol. Ethanol has good solubility and volatility, can effectively remove impurities, and does not cause pollution to the product. Ethanol is volatile, which facilitates subsequent drying and avoids solvent residue affecting product quality.

[0020] The reaction mechanism of the present invention is as follows:

[0021] First, 3-(bromomethyl)-5-methylhexane-2-one undergoes an elimination reaction under the action of a base to obtain A, and then the carbonyl group in A undergoes tautomerism to obtain the enol form B. B is deprotonated under the action of the base to obtain an oxygen anion C, which undergoes tautomerism again to obtain a methyl anion D. D undergoes an addition reaction with 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline to obtain an amino anion E. Subsequently, the amino anion E undergoes an intramolecular Michael addition reaction with the α, β-unsaturated ketone in the structure to obtain an oxygen anion F. The oxygen anion F accepts a proton to obtain an enol structure G, and finally G undergoes tautomerism to obtain deuterated tetrabenazine; the details are as follows:

[0022]

[0023] The beneficial effects of the present invention are: reasonable design, simple preparation method, and specifically include the following advantages:

[0024] (1) Efficient deuterium introduction: 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) and 3-(bromomethyl)-5-methylhexane-2-one are used as raw materials, and an addition elimination reaction occurs in a solvent. After post-treatment, deuterated tetrabenazine is obtained, avoiding the complexity of subsequent deuteration steps and interference from isotope effects. The purity of the obtained deuterated tetrabenazine reaches more than 99.0%, greatly improving the deuteration rate and chemical purity;

[0025] (2) Process controllability: By optimizing parameters such as solvent, ratio, temperature, and time, the reaction is ensured to be efficient and stable, suitable for large-scale production, and avoiding tedious steps such as vacuum distillation (which may directly cause the product to decompose into other substances);

[0026] (3) Simple purification: step-by-step post-processing and purification design (water crystallization + solvent refining) effectively remove impurities without complex chromatographic separation, reducing costs;

[0027] (4) Product quality: The final product meets pharmaceutical standards, has a stable deuterated position, uniform crystal form, and low solvent residue, making it suitable for formulation development. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0029] Figure 1 Deutetrabenazine 1 H-NMR spectrum.

[0030] Figure 2 Deutetrabenazine 13 C-NMR spectrum. DETAILED DESCRIPTION

[0031] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0032] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular also includes the plural. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof.

[0033] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0034] A method for synthesizing deuterated tetrabenazine specifically comprises the following steps:

[0035] Step S1, addition elimination reaction: adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride and 3-(bromomethyl)-5-methylhexane-2-one to a first solvent, and causing an addition elimination reaction under base catalysis to obtain a finished reactant system;

[0036] Step S2, post-treatment: adding water to the finished product reaction system obtained in step S1, cooling and crystallizing, filtering, washing with water, draining, and drying to obtain a crude deuterated tetrabenazine;

[0037] Step S3, refining: the crude deuterated tetrabenazine obtained in step S2 is mixed with a refining solvent and refined to obtain a refined system; the refined system is crystallized and filtered in sequence to obtain a filter cake; the filter cake is washed and dried in sequence to obtain a finished deuterated tetrabenazine.

[0038] The finished product deuterated tetrabenazine prepared by the present invention is a white solid.

[0039] In step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline to hydrochloric acid in 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride is 1:1.

[0040] In step S1, the first solvent is selected from one or more of ethanol, isopropanol, methanol, and water; the mass ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to the first solvent is 1:(4-10), preferably 1:6. The present invention uses TLC to monitor the reaction endpoint.

[0041] In step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to 3-(bromomethyl)-5-methylhexane-2-one is 1:(1.2-1.5).

[0042] In step S1, the base catalyst is selected from one or more of potassium carbonate, N,N-diisopropylethylamine, potassium bicarbonate, and sodium hydroxide.

[0043] In step S1, the reaction temperature of the addition-elimination reaction is 30-50° C., and the reaction time is 16-48 h, preferably 20-24 h.

[0044] In step S2, the crystallization temperature is preferably 0 to 5°C, more preferably 2 to 5°C.

[0045] In step S3, the refining solvent is selected from one or more of ethanol, methanol, and water; the mass ratio of the crude deuterated tetrabenazine to the refining solvent is 1:(3-8), preferably 1:5.

[0046] In step S3, the refining temperature is 50° to 80°C, and the refining time is 0.5 to 2 hours.

[0047] In step S3, the crystallization temperature is 0-5°C.

[0048] In step S3, the solvent used for washing the filter cake is ethanol.

[0049] In step S1 and step S3, drinking water is used.

[0050] In the present invention, the purity of the crude deuterated tetrabenazine obtained in step S2 can reach up to 98.291%, and the yield can reach up to 98.01%; the purity of the deuterated tetrabenazine obtained in step S3 can reach up to 99.902%, and the yield can reach up to 98.85%.

[0051] In the present invention, unless otherwise specified, all raw material components are commercially available commodities well known to those skilled in the art.

[0052] Example 1

[0053] A method for synthesizing deuterated tetrabenazine, specifically:

[0054] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 140.4g of ethanol were added, stirred for 10min, potassium carbonate (41.4g, 0.30mol) was added, stirred for 10min, and 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 15.74g, yield: 48.66%, HPLC purity: 95.396%).

[0055] The building-up reaction of Example 1 is:

[0056]

[0057] Example 2

[0058] A method for synthesizing deuterated tetrabenazine, specifically:

[0059] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 70.2g ethanol + 70.2 water were added, stirred for 10min, potassium carbonate (41.4g, 0.30mol) was added, stirred for 10min, and 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 25.65g, yield: 79.30%, HPLC purity: 96.996%).

[0060] The building-up reaction of Example 2 is:

[0061]

[0062] Example 3

[0063] A method for synthesizing deuterated tetrabenazine, specifically:

[0064] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 70.2g methanol + 70.2 water were added, stirred for 10min, potassium carbonate (41.4g, 0.30mol) was added, stirred for 10min, and 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 31.70g, yield: 98.01%, HPLC purity: 98.291%).

[0065] The building-up reaction of Example 3 is:

[0066]

[0067] Example 4

[0068] A method for synthesizing deuterated tetrabenazine, specifically:

[0069] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 70.2g methanol + 70.2 water were added, stirred for 10min, and DIPEA (38.78g, 0.30mol) was added. After stirring for 10min, 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 11.70g, yield: 36.17%, HPLC purity: 93.291%).

[0070] The building-up reaction of Example 4 is:

[0071]

[0072] Example 5

[0073] A method for synthesizing deuterated tetrabenazine, specifically:

[0074] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 70.2g methanol + 70.2 water were added, stirred for 10min, and then sodium hydroxide (12.0g, 0.30mol) was added. After stirring for 10min, 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 21.70g, yield: 67.09%, HPLC purity: 95.269%).

[0075] The building-up reaction of Example 5 is:

[0076]

[0077] Example 6

[0078] A method for synthesizing deuterated tetrabenazine, specifically:

[0079] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 35.1g methanol + 105.3g water were added, stirred for 10min, potassium carbonate (41.4g, 0.30mol) was added, stirred for 10min, and 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 29.68g, yield: 91.76%, HPLC purity: 96.784%).

[0080] The building-up reaction of Example 6 is:

[0081]

[0082] Example 7

[0083] A method for synthesizing deuterated tetrabenazine, specifically:

[0084] In a 500mL three-necked flask, 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride (1:1) (23.4g, 0.10mol) and 105.3g methanol + 35.1g water were added, stirred for 10min, potassium carbonate (41.4g, 0.30mol) was added, stirred for 10min, and 3-(bromomethyl)-5-methylhexane-2-one (26.9g, 0.13mol) was added. After the addition, the temperature was raised to 40°C and the reaction was kept warm for 24 hours. The reaction end point was monitored by HPLC. 30g of water was added to the reaction system, the temperature was lowered to 3°C, crystallized overnight, filtered, washed with water, and dried in vacuo at 55°C to obtain crude deutetrabenazine (white solid, 30.75g, yield: 95.06%, HPLC purity: 96.788%).

[0085] The building-up reaction of Example 7 is:

[0086]

[0087] Example 8

[0088] A method for synthesizing deuterated tetrabenazine, specifically:

[0089] In a 500 mL three-necked flask, crude deuterated tetrabenazine (32.3 g and 161.5 g of ethanol were added, and the temperature was raised to 70°C after the addition, stirred for 1 h, cooled to 3°C, and crystallized overnight. The product was filtered, washed with ethanol, and dried in vacuo at 55°C to obtain crude deuterated tetrabenazine (white solid, 31.98 g, yield: 98.85%, HPLC purity: 99.902%).

[0090] The building-up reaction of Example 8 is:

[0091]

[0092] Example 9

[0093] A method for synthesizing deuterated tetrabenazine, specifically:

[0094] In a 500 mL three-necked flask, crude deuterated tetrabenazine (32.3 g and 161.5 g of methanol were added. After the addition, the temperature was raised to 70°C, stirred for 1 h, cooled to 3°C, crystallized overnight, filtered, washed with ethanol, and dried in vacuo at 55°C to obtain crude deuterated tetrabenazine (white solid, 29.98 g, yield: 92.82%, HPLC purity: 99.856%).

[0095] The building-up reaction of Example 9 is:

[0096]

[0097] Example 10

[0098] A method for synthesizing deuterated tetrabenazine, specifically:

[0099] In a 500 mL three-necked flask, crude deuterated tetrabenazine (32.3 g and 80.75 g ethanol + 80.75 g water was added, and the temperature was raised to 70°C after the addition, stirred for 1 h, cooled to 3°C, crystallized overnight, filtered, washed with ethanol, and dried in vacuo at 55°C to obtain crude deuterated tetrabenazine (white solid, 29.72 g, yield: 92.00%, HPLC purity: 98.856%).

[0100] The building-up reaction of Example 10 is:

[0101]

[0102] Example 11

[0103] A method for synthesizing deuterated tetrabenazine, specifically:

[0104] In a 500 mL three-necked flask, crude deuterated tetrabenazine (32.3 g and 129.2 g ethanol + 32.3 g water was added, and the temperature was raised to 70°C after the addition, stirred for 1 h, cooled to 3°C, crystallized overnight, filtered, washed with ethanol, and dried in vacuo at 55°C to obtain crude deuterated tetrabenazine (white solid, 30.80 g, yield: 95.36%, HPLC purity: 99.105%).

[0105] The building-up reaction of Example 11 is:

[0106]

[0107] Example 12

[0108] A method for synthesizing deuterated tetrabenazine, specifically:

[0109] In a 500 mL three-necked flask, crude deuterated tetrabenazine (32.3 g and 32.3 g ethanol + 129.2 g water was added, and the temperature was raised to 70°C after the addition, stirred for 1 h, cooled to 3°C, crystallized overnight, filtered, washed with ethanol, and dried in vacuo at 55°C to obtain crude deuterated tetrabenazine (white solid, 31.83 g, yield: 98.53%, HPLC purity: 98.827%).

[0110] The synthesis reaction of Example 12 is:

[0111]

[0112] Figure 1 Deutetrabenazine 1 H-NMR spectrum. Figure 1It can be seen that there are 13 groups of peaks in the figure, of which δ = 2.50 is the peak of the solvent DMSO-d6, δ = 3.3 is the peak of water in the solvent, δ = 6.69 is the peak of the two hydrogens on the benzene ring in the deuterated tetrabenazine structure, δ = 3.46 is the peak of the hydrogen on the benzyl group close to the N atom, δ = 3.24 and δ = 3.12 are the peaks of the benzyl group, δ = 2.88 is the peak of the methylene group connected to the benzyl group and close to the N atom, δ = 2.64 is the peak of the methylene group close to the N atom, δ = 2.46 is the peak of the methylene group close to the carbonyl group, δ = 2.28 is the peak of the methine group close to the carbonyl group, δ = 1.64 is the peak of the methylene group, δ = 0.92 is the peak of the methine group, and δ = 0.87 is the peak of the methyl group; therefore, the nuclear magnetic data is 1 H NMR (400MHz, DMSO-d6): δ6.69 (s, 2H), 3.46 (d, J = 12Hz, 1H), 3.24-3.22 (m, 1H), 3.14-3.10 (m, 1H), 2.92-2.83 (m, 2H), 2. 69-2.65(m,2H),2.46(t,J=12Hz,2H),2.28(t,J=15Hz,1H),1.66-1.61(m,2H),0.92(t,J=8Hz,1H),0.87(q,J=4Hz,6H). Figure 1 It can be proved that what is prepared in the present invention is deuterated tetrabenazine.

[0113] Figure 2 Deutetrabenazine 13 C-NMR spectrum. Figure 2 It can be seen that there are 20 groups of peaks in the figure, among which δ=40 is the peak of the solvent DMSO-d6, δ=209.88 is the peak of the carbonyl carbon in the deuterated tetrabenazine structure, δ=147.79 and δ=147.55 are the peaks of the carbon on the benzene ring connected to the deuterated methoxy group, δ=129.31 and δ=126.23 are the peaks of the carbon on the benzene ring connected to the benzyl group, δ=112.18 and δ=109.29 are the peaks of the carbon on the benzene ring, δ=62.15 is the peak of the carbon on the benzyl group close to the N atom, δ=61.05 is the peak of the methylene group close to the N atom. The peaks of the carbon of the deuterated methyl group are as follows: δ = 55.25 and δ = 55.05 are the peaks of the methyl carbon in the deuterated methyl group, δ = 49.61 is the peak of the methylene carbon connected to the benzyl group and close to the N atom, δ = 47.03 is the peak of the methylene carbon close to the carbonyl group, δ = 46.74 is the peak of the methine carbon close to the carbonyl group, δ = 35.33 is the peak of the methylene carbon, δ = 29.37 is the peak of the benzyl carbon, δ = 25.40 is the peak of the methine carbon, δ = 23.54 and δ = 22.66 are the peaks of the methyl carbon; therefore, the NMR data are13 C NMR (100MHz, DMSO-d6): δ209.88, 147.79, 147.55, 129.31, 126.23, 112.18, 109.29, 6 2.15, 61.05, 55.25, 55.05, 49.61, 47.03, 46.74, 35.33, 29.37, 25.40, 23.54, 22.66. Figure 2 It is further explained that the present invention prepares deuterated tetrabenazine.

[0114] In summary, the present invention provides a method for synthesizing deuterated tetrabenazine. By optimizing reaction conditions, selecting appropriate solvents and catalysts, and performing meticulous post-processing and purification steps, the synthesis of a target product with high yield and high purity is achieved. This method has the advantages of readily available raw materials, low cost, efficient reaction, high conversion rate, and environmental friendliness. It also has a short process route, is simple to operate, and is suitable for industrial production. Furthermore, the present invention ensures product quality and stability by clarifying the technical parameters and conditions of each step, providing strong technical support for the industrial production of deuterated tetrabenazine.

[0115] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing deutetrabenazine, characterized in that: The specific steps include: Step S1, addition elimination reaction: adding 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride and 3-(bromomethyl)-5-methylhexane-2-one to a first solvent, and causing an addition elimination reaction under base catalysis to obtain a finished reactant system; Step S2, post-treatment: adding water to the finished product reaction system obtained in step S1, cooling and crystallizing, filtering, washing with water, draining, and drying to obtain a crude deuterated tetrabenazine; Step S3, refining: the crude deuterated tetrabenazine obtained in step S2 is mixed with a refining solvent and refined to obtain a refined system; the refined system is crystallized and filtered in sequence to obtain a filter cake; the filter cake is washed and dried in sequence to obtain a finished deuterated tetrabenazine.

2. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In the step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline to hydrochloric acid in 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride is 1:

1.

3. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In step S1, the first solvent is selected from one or more of ethanol, isopropanol, methanol, and water; and the mass ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to the first solvent is 1:(4-10).

4. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In the step S1, the molar ratio of 6,7-bis(methoxy-d3)-3,4-dihydroisoquinoline hydrochloride to 3-(bromomethyl)-5-methylhexane-2-one is 1:(1.2-1.5).

5. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In step S1, the base catalyst is selected from one or more of potassium carbonate, N,N-diisopropylethylamine, potassium bicarbonate, and sodium hydroxide.

6. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In step S1, the reaction temperature of the addition-elimination reaction is 30-50° C., and the reaction time is 16-48 hours.

7. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In step S3, the refining solvent is selected from one or more of ethanol, methanol, and water; and the mass ratio of the crude deuterated tetrabenazine to the refining solvent is 1:(3-8).

8. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In step S3, the refining temperature is 50° to 80° C., and the refining time is 0.5 to 2 hours.

9. A method for synthesizing deutetrabenazine according to claim 1, characterized in that: In the step S3, the crystallization temperature is 0-5°C.

10. The method for synthesizing deutetrabenazine according to claim 1, wherein: In step S3, the solvent used for washing the filter cake is ethanol.

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