A preparation method of dexmedetomidine hydrochloride intermediate

Abstract

The present invention provides a preparation method of a dexmedetomidine intermediate, comprising the steps of: (1) dissolving Lewis acid in an aprotic organic solvent, cooling to below 10 DEG C, dripping N-Boc-imidazole dissolved in an aprotic organic solvent, controlling the temperature below 10 DEG C, and mixing uniformly; (2) dripping 1-(1-chloroethyl)-2,3-dimethylbenzene, heating to 0-45 DEG C after completion of the dropwise addition until the reaction is complete, adding water or an inorganic acid aqueous solution to quench, adding an aprotic organic solvent to extract, collecting and merging the extracted organic layer; (3) adding a poor solvent to the organic layer, the product is precipitated, and dried to obtain. The preparation method of the present invention significantly reduces side reactions and by-products by optimizing the feed ratio and reaction conditions, significantly reduces production costs, and has a high yield and stable process, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a dexmedetomidine hydrochloride intermediate. Background Art

[0002] Dexmedetomidine hydrochloride is a clinical sedative. According to literature reports, dexmedetomidine is prepared by splitting the racemic form of medetomidine. Therefore, medetomidine is a key intermediate for preparing dexmedetomidine. In the early days, the conditions used in the synthesis method of medetomidine were relatively harsh, for example, using n-butyl lithium (J Chem Soc Perkin Trans, 1984, (3): 481-486) ​​or Grignard reagent (CN103664788A).

[0003] CN105254567A discloses the preparation of medetomidine by Lewis acid catalysis using 1-(1-chloroethyl)-2,3-dimethylbenzene and N-Boc-imidazole as raw materials in an aprotic organic solvent in the presence of an acid binding agent. However, this method has the following defects: (1) The feed ratio of the two reaction substrates 1-(1-chloroethyl)-2,3-dimethylbenzene:N-Boc-imidazole is 1:1-1:0.5, resulting in incomplete reaction, and many by-products, and the material price of the former is much higher than that of the latter, resulting in high production costs. (2) The acid binding agent is used, and the acid binding agent forms a salt with the Lewis acid in the reaction solvent, resulting in high viscosity of the reaction material, difficulty in stirring, deposition of a large amount of material, low material conversion rate, and decreased yield. At the same time, the salt formed is difficult to handle, which prolongs the production cycle and increases the difficulty of three wastes and three waste treatment, resulting in higher production costs. (3) The process is unstable, the yield consistency is poor, and it is impossible to meet the needs of industrial production. For this reason, it is necessary to develop a preparation process suitable for industrial production and with more reasonable cost. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing a dexmedetomidine intermediate (structure shown in Formula 1), comprising the following steps:

[0005]

[0006] (1) dissolving a Lewis acid in an aprotic organic solvent, cooling the temperature to below 10° C., adding dropwise N-Boc-imidazole dissolved in the aprotic organic solvent, controlling the temperature to below 10° C., and mixing uniformly;

[0007] (2) adding 1-(1-chloroethyl)-2,3-dimethylbenzene dropwise, raising the temperature to 0-45° C. after the addition is complete until the reaction is complete, adding water or an aqueous solution of an inorganic acid to quench, adding an aprotic organic solvent to extract, and collecting and combining the extracted organic layers;

[0008] (3) Add a poor solvent to the organic layer, the product precipitates, and is dried to obtain the product.

[0009] In the preferred technical scheme of the present invention, in the reaction system, the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene:N-Boc-imidazole:Lewis acid is 1:1.5:0.9-1:3:1.5, preferably 1:1.5:1-1:3:1.1, and more preferably 1:2:1.

[0010] In the preferred technical solution of the present invention, the Lewis acid is selected from any one of titanium tetrachloride, AlCl3, SbCl5, CeCl3, SbCl3, SnCl4, BF3·OEt2, TiCl4, and ZnCl2, or a combination thereof.

[0011] In the preferred technical solution of the present invention, the aprotic organic solvent is selected from one of dichloromethane, chloroform, ether, carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, nitrobenzene or a combination thereof.

[0012] In the preferred technical solution of the present invention, the inorganic acid includes but is not limited to one of hydrochloric acid, sulfuric acid, nitric acid or a combination thereof.

[0013] In the preferred technical solution of the present invention, the mixing method in step (1) is selected from stirring, oscillating or a combination thereof.

[0014] In the preferred technical solution of the present invention, the mixing time is not less than 0.1 hour, preferably not less than 0.5 hour.

[0015] In the preferred technical solution of the present invention, the cooling temperature in step (1) is -20-10°C, preferably -5-5°C.

[0016] In the preferred technical solution of the present invention, the temperature of step (1) is controlled at -20-10°C, preferably 0-10°C.

[0017] In the preferred technical solution of the present invention, the temperature of the dropwise addition process in step (2) is controlled at -20-10°C, more preferably 0-10°C.

[0018] In the preferred technical solution of the present invention, the temperature of step (2) is raised to 10-30°C for reaction, preferably 15-25°C.

[0019] In the preferred technical solution of the present invention, the temperature of step (2) is lowered to below 25°C, preferably 0-10°C, after the reaction is quenched.

[0020] In the preferred technical solution of the present invention, the reaction time of step (2) is 1-10 h, preferably 1-5 h.

[0021] In the preferred technical solution of the present invention, the extraction times in step (2) is no less than 1 time, preferably 2-3 times.

[0022] In the preferred technical solution of the present invention, the extraction solvent in step (2) is selected from any one of dichloromethane, chloroform, ether, carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, nitrobenzene or a combination thereof.

[0023] In the preferred technical solution of the present invention, the poor solvent in step (3) is selected from any one of n-heptane, n-hexane, cyclohexane, and methyl tert-butyl ether, or a combination thereof.

[0024] In the preferred technical solution of the present invention, after adding the poor solvent in step (3), the temperature is lowered to below 10°C, preferably 0-5°C.

[0025] In the preferred technical solution of the present invention, the cooling operation in step (3) can be performed before or after the product precipitates.

[0026] In the preferred technical solution of the present invention, the drying method of step (3) is selected from any one of vacuum drying, reduced pressure drying, normal pressure drying, spray drying, and boiling drying, or a combination thereof.

[0027] In the preferred technical solution of the present invention, the precipitated product is separated and collected, and the preferred separation method is selected from any one of filtration, centrifugation, membrane treatment or a combination thereof.

[0028] In the preferred technical solution of the present invention, the precipitated product is dried after purification, and the preferred purification method is recrystallization.

[0029] In the preferred technical solution of the present invention, the recrystallization is performed at least once, preferably 2-3 times.

[0030] In the preferred technical solution of the present invention, the crystallization purification solvent is selected from any one of acetone, toluene, acetonitrile, tetrahydrofuran or a combination thereof.

[0031] In the preferred technical solution of the present invention, the collected separated solid is washed and then dried, and the solvent used for washing is preferably selected from any one of acetone, acetonitrile, toluene, tetrahydrofuran, n-heptane, n-hexane, cyclohexane, methyl tert-butyl ether or a combination thereof.

[0032] The present invention also aims to provide the use of the dexmedetomidine intermediate of the structure shown in Formula 1 in the preparation of medetomidine, dexmedetomidine or a salt thereof.

[0033] In the preferred technical solution of the present invention, the medetomidine is prepared by neutralizing the dexmedetomidine intermediate of the structure shown in Formula 1 with an inorganic base. The inorganic base is selected from any one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate, lithium hydroxide or a combination thereof.

[0034] In the preferred technical solution of the present invention, the dexmedetomidine is prepared by directed synthesis of medetomidine and a chiral reagent. The chiral reagent includes but is not limited to (+)-tartaric acid, S-binaphthol phosphate (S-(+)BNP), D-(+)-dibenzoyltartaric acid, D-(-)-tartaric acid or a combination thereof.

[0035] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0036] Compared with the prior art, the present invention has the following beneficial technical effects:

[0037] 1. The preparation method of the present invention optimizes the feed ratio and reaction conditions, increases the feed amount of cheap N-Boc-imidazole, significantly improves the reaction conversion rate of expensive 1-(1-chloroethyl)-2,3-dimethylbenzene, and eliminates the use of acid-binding agents, significantly reduces side reactions and by-products, significantly shortens the preparation cycle, and significantly reduces the generation of three wastes and the amount of three wastes recovered and processed, thereby significantly reducing the production cost, and is suitable for large-scale industrial production.

[0038] 2. The preparation method of the present invention has the advantages of simple operation, high yield and stable process, few by-products and low cost, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 Carbon spectrum of the dexmedetomidine intermediate (Formula 1) prepared in Example 1

[0040] Figure 2 Hydrogen spectrum of the dexmedetomidine intermediate (Formula 1) prepared in Example 1

[0041] Figure 3 Mass spectrum of the dexmedetomidine intermediate (Formula 1) prepared in Example 1 DETAILED DESCRIPTION

[0042] The following are some specific embodiments to illustrate the present invention. It is necessary to point out that the following specific embodiments are only used to further illustrate the present invention and do not limit the protection scope of the present invention. Some non-essential modifications and adjustments made by others based on the present invention still fall within the protection scope of the present invention.

[0043] Comparative Example 1

[0044] With reference to the preparation method of Example 1 of CN105254567A, 1-(1-chloroethyl)-2,3-dimethylbenzene and N-Boc-imidazole were used as raw materials to prepare 3 batches of dexmedetomidine intermediate (Formula 1), as shown in the following table.

[0045] Table 1

[0046]

[0047] Example 1

[0048] Add 100g of dichloromethane and 43.01g of titanium tetrachloride to a 0.5L three-necked flask, cool to -3°C, then drop a pre-prepared dichloromethane solution of N-Boc-imidazole (79.93g), control the internal temperature at 0-3°C, and stir at 3-5°C for 0.5h after the addition is complete. Continue to slowly drop 38.08g of 1-(1-chloroethyl)-2,3-dimethylbenzene, control the internal temperature at 5-8°C, and heat to 22°C for 3h after the addition is complete. Cool the system to 2-5°C, drop 160g of purified water to quench the reaction, and control the internal temperature at 17-20°C. Add 400g of dichloromethane and stir thoroughly for 1-2h, let stand and separate, extract the aqueous phase with 140g of dichloromethane x2 twice, combine all dichloromethane phases, and evaporate dichloromethane by rotary evaporation at 40℃ under reduced pressure (vacuum degree ≥ 0.08MPa) until no obvious droplets fall, to obtain an oily substance, add 50g of dichloromethane and stir to dissolve the oily substance, slowly add dropwise to a three-necked flask containing 300g of n-heptane at 22℃, cool to 3℃ and stir for 1h after solid precipitation, filter, rinse the filter cake with 60g of n-heptane, drain, collect the filter cake and add it to a 1L three-necked flask, add 132g of acetone, beat at 3℃ for 2h, filter, rinse the filter cake with 32g of acetone, drain, dry at 40℃ under vacuum (vacuum degree ≥ 0.08MPa), and obtain constant weight after 4h, with HPLC purity of 98.3% and yield of 77.5%. See the attached structure confirmation spectrum for details. Figure 1-3 .

[0049] Example 2

[0050] Add 100g of dichloromethane and 42.82g of titanium tetrachloride to a 0.5L three-necked flask, cool to -10°C, then drop a pre-prepared dichloromethane solution of N-Boc-imidazole (71.94g), control the internal temperature at -6 to -3°C, and stir at -2°C for 1.0h after the addition is complete. Continue to slowly drop 40.08g of 1-(1-chloroethyl)-2,3-dimethylbenzene, control the internal temperature at 8-10°C, and heat to 42°C for 2h after the addition is complete. Cool the system to 0-10°C, drop 160g of purified water to quench the reaction, and control the internal temperature at 15-18°C. Add 400g of dichloromethane and stir thoroughly for 1-2h, let stand and separate the liquids, extract the aqueous phase twice with 136g of dichloromethane x2, combine all dichloromethane phases, and evaporate dichloromethane under reduced pressure at 40°C (vacuum degree ≥0.08MPa) until no obvious droplets fall to obtain an oily substance, add 50g of dichloromethane and stir to dissolve the oily substance, slowly add dropwise to a three-necked flask containing 300g of n-heptane at 20°C, cool to 2°C and stir for 1h after solid precipitation, filter, rinse the filter cake with 60g of n-heptane, drain, collect the filter cake and add it to a 1L three-necked flask, add 132g of acetone, beat at 3°C ​​for 2h, filter, rinse the filter cake with 32g of acetone, drain, dry, and dry in vacuum at 40°C (vacuum degree ≥0.08MPa). Constant weight is obtained after 4h, and the HPLC purity is 95.06% and the yield is 74.7%.

[0051] Example 3

[0052] Add 100g of dichloromethane and 55.72g of titanium tetrachloride to a 0.5L three-necked flask, cool to 3°C, then drop a pre-prepared dichloromethane solution of N-Boc-imidazole (75.04g), control the internal temperature at -10 to -7°C, and stir at -8°C for 0.1h after the addition is complete. Continue to slowly drop 50.08g of 1-(1-chloroethyl)-2,3-dimethylbenzene, control the internal temperature at 0-3°C, and heat to 25-27°C for 3h after the addition is complete. Cool the system to 0-3°C, drop 160g of purified water to quench the reaction, and control the internal temperature at 8-10°C. Add 400g of dichloromethane and stir thoroughly for 1-2h, let stand and separate the liquids, extract the aqueous phase twice with 135g of dichloromethane x2, combine all dichloromethane phases, and evaporate the dichloromethane under reduced pressure (vacuum degree ≥0.08MPa) at 40°C until no obvious droplets fall to obtain an oily substance, add 48g of dichloromethane and stir to dissolve the oily substance, slowly add dropwise to a three-necked flask containing 355g of n-heptane at 20°C, cool to 4°C and stir for 1h after solid precipitation, filter, rinse the filter cake with 65g of n-heptane, drain, collect the filter cake and add it to a 1L three-necked flask, add 153g of acetone, slurry at 3°C ​​for 2h, filter, rinse the filter cake with 35g of acetone, drain, dry it, and dry it in vacuum at 40°C (vacuum degree ≥0.08MPa). Constant weight is obtained after 4h, and the HPLC purity is 96.09% and the yield is 78.9%.

[0053] Example 4

[0054] Add 100g of dichloromethane and 35.72g of aluminum chloride to a 0.5L three-necked flask, cool to -5°C, then drop a pre-prepared dichloromethane solution of N-Boc-imidazole (90.04g), control the internal temperature at 0-2°C, and stir at 0°C for 1.0h after the addition is complete. Continue to slowly drop 30.08g of 1-(1-chloroethyl)-2,3-dimethylbenzene, control the internal temperature at 8-10°C, and heat to 33°C for 2h after the addition is complete. Cool the system to 5-10°C, drop 160g of purified water to quench the reaction, and control the internal temperature at 20-22°C. Add 400g of dichloromethane and stir thoroughly for 1-2h, let stand and separate the liquids, extract the aqueous phase twice with 136g of dichloromethane x2, combine all dichloromethane phases, and evaporate dichloromethane under reduced pressure (vacuum degree ≥0.08MPa) at 40°C until no obvious droplets fall to obtain an oily substance, add 50g of dichloromethane and stir to dissolve the oily substance, slowly add dropwise to a three-necked flask containing 400g of n-heptane at 20°C, cool to 2°C and stir for 1h after solid precipitation, filter, rinse the filter cake with 80g of n-heptane, drain, collect the filter cake and add it to a 1L three-necked flask, add 140g of acetone, beat at 3°C ​​for 2h, filter, rinse the filter cake with 45g of acetone, drain, dry, and dry in vacuum at 40°C (vacuum degree ≥0.08MPa). Constant weight is obtained after 4h, and the HPLC purity is 97.12% and the yield is 79.1%.

[0055] Example 5

[0056] Add 2.5kg of dichloromethane and 1.12kg of titanium tetrachloride to a 20L reactor, cool to -3°C, then drop a pre-prepared dichloromethane solution of N-Boc-imidazole (2.39kg), control the internal temperature at 0-3°C, and stir at 4°C for 0.5h after the addition is complete. Continue to slowly drop 1.0kg of 1-(1-chloroethyl)-2,3-dimethylbenzene, control the internal temperature at 5-8°C, and heat to 23°C for 3h after the addition is complete. Cool the system to 2-5°C, drop 4.0kg of purified water to quench the reaction, and control the internal temperature at 20-22°C. Add 10kg of dichloromethane and stir thoroughly for 1-2h, let stand and separate the liquids, extract the aqueous phase twice with 3.4kg x2 of dichloromethane, combine all dichloromethane phases, and evaporate dichloromethane by rotary evaporation under reduced pressure (vacuum degree ≥ 0.08MPa) at 40°C until no obvious droplets fall to obtain an oily substance, add 1.25kg of dichloromethane and stir to dissolve the oily substance, slowly add dropwise to a 20L reactor containing 7.5kg of n-heptane at 23°C, cool to 3°C and stir for 1h after solid precipitation, filter, rinse the filter cake with 1.5kg of n-heptane, drain, collect the filter cake and add it to a 5L three-necked flask, add 3.2kg of acetone, slurry at 3°C ​​for 2h, filter, rinse the filter cake with 0.8kg of acetone, drain, dry in vacuum at 40°C (vacuum degree ≥ 0.08MPa), and obtain constant weight after 4h. The HPLC purity is 96.0% and the yield is 80.5%.

Claims

1. A method for preparing a dexmedetomidine intermediate having a structure shown in formula 1, comprising the following steps: (1) dissolving a Lewis acid in an aprotic organic solvent, cooling the temperature to below 10° C., adding dropwise N-Boc-imidazole dissolved in the aprotic organic solvent, controlling the temperature to below 10° C., and stirring uniformly; (2) adding 1-(1-chloroethyl)-2,3-dimethylbenzene dropwise, raising the temperature to 0-45° C. until the reaction is complete, adding water to quench, adding an aprotic organic solvent for extraction, and collecting and combining the extracted organic layers; (3) Add a poor solvent to the organic layer, precipitate the product, and dry it to obtain: In the reaction system, the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene:N-Boc-imidazole:Lewis acid is 1:1.5:0.9-1:3:1.

5.

2. The preparation method according to claim 1, characterized in that The Lewis acid is selected from any one of titanium tetrachloride, AlCl3, SbCl5, CeCl3, SbCl3, SnCl4, BF3·OEt2, TiCl4, and ZnCl2; and the aprotic organic solvent is selected from one of dichloromethane, chloroform, ether, carbon tetrachloride, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and nitrobenzene.

3. The preparation method according to claim 2, characterized in that: The stirring time of step (1) is not less than 0.1 hour; the cooling temperature of step (1) is -20-10°C; the temperature control temperature of step (1) is -20-10°C.

4. The preparation method according to claim 3, characterized in that: The temperature of the dropwise addition process in step (2) is controlled at 0-10°C; the temperature in step (2) is raised to 10-30°C for reaction; the reaction time in step (2) is 2-3h; the number of extractions in step (2) is 2-3 times; the extraction solvent in step (2) is selected from dichloromethane.

5. The preparation method according to claim 4, characterized in that: The poor solvent in step (3) is selected from n-heptane; after adding the poor solvent in step (3), the temperature is lowered to 0-5°C; the cooling operation in step (3) is performed after the product is precipitated; and the drying method in step (3) is selected from vacuum drying.

6. The preparation method according to claim 5, characterized in that: The precipitated product is separated and collected, and then purified and dried. The purification method is recrystallization, and the crystallization purification solvent is acetone.

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