A preparation method of dexmedetomidine hydrochloride

Abstract

The invention discloses a preparation method of dexmedetomidine hydrochloride. First, 2', 3'-dimethylacetophenone is used as raw material. Under Lewis acid catalysis, chlorination reaction occurs with dimethylchlorosilane to synthesize 1-(1-chloroethyl)-2,3-dimethylbenzene. Then, under chiral catalyst catalysis, cross-reduction coupling reaction occurs with 4-iodoimidazole, and finally salification is performed to obtain dexmedetomidine hydrochloride with an enantiomeric excess of up to 99%. The method has the advantages of easy availability of raw materials, simple operation, mild reaction conditions, short synthesis route, high yield, good stereoselectivity, and good economic and social benefits.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of dexmedetomidine hydrochloride. Background Art

[0002] Dexmedetomidine, also known as dexmedetomidine hydrochloride, has a chemical name of (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. It is an adrenergic α2 receptor agonist jointly developed by Abott of the United States and Orion Pharma of Finland. It was first launched in the United States in March 2000. Dexmedetomidine is a highly effective and selective α2 receptor agonist with a unique type of sedation, that is, the sedated state can be awakened and almost no respiratory depression is caused during the sedation process. Due to its excellent sedative and hypnotic effects and good safety, dexmedetomidine is widely used in many fields such as sedation and analgesia for patients in intensive care, preoperative medication, adjuvant medication for general anesthesia, and postoperative analgesia. The structural formula is shown below:

[0003]

[0004] Currently, the methods for preparing dexmedetomidine can be divided into two main categories: one involves the construction of an imidazole ring during the synthesis process, such as the methods shown in patents WO 2013014428 A1 and WO2016120635 A1; the second involves the synthesis of two fragments, an imidazole ring and a benzene ring, such as the methods shown in patents US20100048915 A1. The methods involving the construction of an imidazole ring to synthesize dexmedetomidine have the following defects: (1) 3-4 steps are required to synthesize dexmedetomidine, the synthesis route is too long, and the total yield of synthesized dexmedetomidine is only 16%; (2) the reaction involves Grignard reaction, coupling reaction, etc., the operation is relatively cumbersome, and the reaction conditions are relatively harsh; (3) high temperature and high pressure are used in the process of constructing the imidazole ring, which is not conducive to industrial scale-up production. Therefore, this type of method has not yet been applied to the industrial production of dexmedetomidine.

[0005] In addition, the literature Synthetic Communications 1996, 26 (8), 1585-1593, patent US20100048915A1, CN 105884691 A, and CN 106083724A reported the use of a halogenated compound of one of the aromatic fragments to prepare a corresponding Grignard reagent, which was then added to an aromatic ketone or aldehyde of another fragment, and then dexmedetomidine was obtained through several steps of reaction. In this type of route for synthesizing dexmedetomidine from an aromatic halide and an aromatic aldehyde or ketone, the Grignard reaction is used, which is relatively strict in the anhydrous operation of the process, and the reaction steps are long and the operation is relatively cumbersome. Patent CN 105254567 A discloses an alkylation reaction using N-Boc-imidazole and 1-(1-chloroethyl)-2,3-dimethylbenzene as raw materials and titanium tetrachloride as a Lewis acid. The reaction directly synthesizes dexmedetomidine in one step with a yield of 73%, which is then resolved with tartaric acid to synthesize dexmedetomidine hydrochloride. When this method uses a large amount of strong Lewis acid, the water content in the process needs to be strictly controlled. In particular, when titanium tetrachloride is used, there is a strong smoke phenomenon. These methods all use splitting to obtain chiral molecules, but the highest splitting yield is only 50%, which is not conducive to commercial production.

[0006] Patents CN 108147999 A and CN 109912508 A disclose the synthesis of dexmedetomidine using asymmetric hydrogenation strategies using a metal rhodium salt and a chiral bisphosphine ligand as catalysts. This asymmetric catalytic method significantly increases raw material utilization, but the synthesis of the key intermediate 4-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole is relatively cumbersome, and the chiral bisphosphine catalysts used in the asymmetric hydrogenation are expensive and require high catalyst quantities. Patent CN 108147999 A uses a 0.2 mol% catalytic amount, but chiral control is insufficient, requiring a further resolution to obtain dexmedetomidine with >99% ee. Patent CN 109912508 A uses a 1 mol% catalytic amount, which, considering the catalyst cost, is not suitable for industrial-scale production.

[0007] Therefore, the current method of synthesizing dexmedetomidine by asymmetric hydrogenation urgently needs to find a convenient method for synthesizing the intermediate 4-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole, as well as a catalyst with low price and good catalytic effect. Summary of the Invention

[0008] The purpose of the present invention is to use 2',3'-dimethylacetophenone 2 as a raw material, a Lewis acid as a catalyst, dimethylchlorosilane 3 as a chlorination reagent, add a solvent, and undergo a chlorination reaction at room temperature to generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4, which is then subjected to a cross-reduction coupling reaction with 4-iodoimidazole 5 under the catalysis of a chiral catalyst, and finally salt is formed to obtain dexmedetomidine hydrochloride compound 1.

[0009] In order to achieve the above object, the technical solution of the present invention is as follows:

[0010] In one aspect, the present invention provides a dexmedetomidine hydrochloride compound, whose molecular structural formula 1 is as follows:

[0011]

[0012] Experimental steps: 1) Using 2',3'-dimethylacetophenone 2 as raw material, Lewis acid as catalyst, dimethylchlorosilane 3 as chlorination reagent, adding solvent, and undergoing chlorination reaction at room temperature to generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4 with different structures. 2) Under the catalysis of a chiral catalyst, a reductive cross-coupling reaction with 4-iodoimidazole 5 is performed, and then a 4N methanol solution of hydrogen chloride is added to the reaction solution to form a salt to obtain the hydrochloride compound 1 of dexmedetomidine. After the reaction is completed, the product is separated and characterized by conventional separation and purification methods to obtain the target product. The specific reaction equation is as follows:

[0013]

[0014] Based on the above technical solution, preferably, the catalyst is one of Fe(ClO4)3, In(OH)3, Fe(acac)3, AlCl3 or FeCl3; wherein, the reaction is best achieved with FeCl3 as a catalyst, and the molar ratio of 2',3'-dimethylacetophenone 2 to the catalyst is 1:0.02-1:0.1, preferably 1:0.05.

[0015] Based on the above technical solution, preferably, the solvent is one or more of 1,4-dioxane, ethyl acetate, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction effect is best when the reaction solvent is ethyl acetate.

[0016] Based on the above technical solution, preferably, the reaction temperature is 0-50°C; the reaction time is 6-48 hours, the optimal reaction time is 12-24 hours; and the optimal reaction temperature is 25°C.

[0017] Based on the above technical solution, preferably, the molar ratio of 2',3'-dimethylacetophenone 2 to dimethylchlorosilane 3 is 1:1-1:2, more preferably 1:1.5.

[0018] In the step 2, the substituent R 1 Same as above: R 1 It is hydrogen, methyl, methoxy, fluorine, chlorine, trifluoromethyl, nitro, or cyano.

[0019] Based on the above technical solution, preferably, the catalyst is one of NiI2, NiBr2, NiSO3CF3, Ni(PPh3)2Cl2, NiCl2, and Ni(COD)2, wherein the reaction is best performed with NiI2 as a catalyst, and the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to the catalyst is 1:0.01-1:0.1, preferably 1:0.1.

[0020] Based on the above technical solution, preferably, the ligand is one of monophosphine ligand (L1-L6), diphosphine ligand (L7-L11), nitrogen phosphine ligand (L12-L13), oxazoline ligand (L14-L19), and pyridine oxazoline ligand (L20-L21); the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 and the ligand is 1:0.0001-1:0.1, preferably 1:0.1.

[0021]

[0022] Based on the above technical solution, the preferred additives are magnesium chloride, pyridine, and zinc powder; the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to the additive is 1:0.01-1:0.2, preferably 1:0.1; the solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylacetamide, or tetrahydrofuran; the optimal reaction solvent is N,N-dimethylacetamide; the reaction temperature is 0-50°C, and the optimal reaction temperature is 25°C; the reaction time is 6-48 hours, and the optimal reaction time is 12-24 hours. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only 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.

[0024] Figure 1 HPLC charts of the dexmedetomidine hydrochloride compound (1) of the present invention; wherein (a) is the HPLC chart of the racemic compound (1), and (b) is the HPLC chart of the chiral compound (1). DETAILED DESCRIPTION

[0025] Example 1

[0026]

[0027] The specific process is as follows: A 50 mL single-necked round-bottom flask was charged with 2',3'-dimethylacetophenone 2 (1.4821 g, 10.0 mmol), ferric chloride (0.0811 g, 0.5 mmol), and EtOAc (20 mL). The reaction mixture was stirred at room temperature for 1 min, and then HMe2SiCl (1.4192 g, 15.0 mmol) was added. Subsequently, the reaction flask was equipped with a 90° glass joint to protect the mixture from moisture. The reaction mixture was stirred vigorously at room temperature until the reaction was complete (detected by thin-layer chromatography (TLC)). The solution was washed with saturated sodium bicarbonate solution (3 × 10 mL) to remove the ferric chloride. The organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under vacuum, and the mixture was purified by column chromatography to obtain 1.35 g of the product 4 compound (80% yield) as a yellow liquid. 1 H NMR (400MHz, CDCl3) δ7.38(d,J=7.2Hz,1H),7.08–7.14(m,2H),5.41(q,J=6.8Hz,1H),2.29(s,3H),2.28(s,3H),1.85(d,J=2.4Hz,3H); 13 C NMR (101MHz, CDCl3) δ144.68,139.34,138.50,131.40,129.11,128.32,59.20,26.32,20.45,18.77.C 10 H 13 HRMS theoretical value of Cl ([M+H] + ):169.0779; measured value:169.0779.

[0028] Example 2

[0029]

[0030] The specific procedure was as follows: 4-iodoimidazole 5 (130.9 mg, 0.3 mmol, 100 mol%) and 1-(1-chloroethyl)-2,3-dimethylbenzene 4 (101.2 mg, 0.6 mmol, 200 mol%) were charged to a flame-dried Schlenk tube equipped with a stir bar. Ligand L19 (10.7 mg, 0.03 mmol, 10 mol%), zinc powder (39.2 mg, 0.6 mmol, 200 mol%), and MgCl2 (28.6 mg, 0.3 mmol, 100 mol%) were then added. The tube was transferred to an anhydrous glove box, and NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was capped with a rubber septum and removed from the glove box. N,N-dimethylacetamide (1 mL) and pyridine (24 μL, 0.3 mmol, 100 mol%) were added using a syringe. The mixture was stirred at 25°C under a N2 atmosphere for 16 hours and then directly loaded onto a silica gel column without further treatment. The residue in the reaction vessel was rinsed with a small amount of petroleum ether. After purification by column chromatography, 4N hydrogen chloride in methanol (75 mL) was added to the effluent. The reaction was stirred at room temperature for 1 hour and filtered to obtain the desired product 1 (60.4 mg, 85% yield, 99% ee).

[0031] Example 3

[0032]

[0033] The reaction steps and operation were the same as those in Example 2, except that the ligand L10 (18.7 mg, 0.03 mmol, 10 mol%) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (38.4 mg, 54% yield, 32% ee).

[0034] Example 4

[0035]

[0036] The reaction steps and operation were the same as those in Example 2, except that the ligand L12 (12.2 mg, 0.03 mmol, 10 mol%) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (43.3 mg, 61% yield, 41% ee).

[0037] Example 5

[0038]

[0039] The reaction steps and operation were the same as those in Example 2, except that the ligand L14 (10.0 mg, 0.03 mmol, 10 mol%) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (51.8 mg, 73% yield, 79% ee).

[0040] Example 6

[0041]

[0042] The reaction steps and operation were the same as those in Example 2, except that the ligand L16 (11.2 mg, 0.03 mmol, 10 mol%) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (54.0 mg, 76% yield, 85% ee).

[0043] Example 7

[0044]

[0045] The reaction steps and operation were the same as those in Example 2, except that the ligand L20 (6.7 mg, 0.03 mmol, 10 mol%) was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (44.7 mg, 63% yield, 65% ee).

[0046] Example 8

[0047]

[0048] The reaction steps and operation were the same as those in Example 2, except that 14.3 mg, 0.15 mmol, 50 mol% MgCl2 was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (56.8 mg, 80% yield, 95% ee).

[0049] Example 9

[0050]

[0051] The reaction steps and operations were the same as those in Example 2, except that 12 μL, 0.15 mmol, 50 mol% pyridine was added to the reaction system. The reaction was stopped and post-processed to obtain the target product 1 (53.3 mg, 75% yield, 90% ee).

[0052] Example 10

[0053]

[0054] The reaction steps and operation were the same as those in Example 2, except that 19.6 mg of zinc powder (0.3 mmol, 100 mol%) was added to the reaction system. The reaction was stopped and the target product 1 (54.7 mg, 77% yield, 88% ee) was obtained after post-treatment.

[0055] Example 11

[0056]

[0057] The specific procedure was as follows: 4-iodoimidazole 5 (2.618 g, 6.0 mmol, 100 mol%) and 1-(1-chloroethyl)-2,3-dimethylbenzene 4 (2.024 g, 12.0 mmol, 200 mol%) were placed in a flame-dried Schlenk flask equipped with a stir bar. Ligand L19 (214.0 mg, 0.6 mmol, 10 mol%), zinc powder (784.0 mg, 12.0 mmol, 200 mol%), and MgCl2 (572.0 mg, 6.0 mmol, 100 mol%) were then added. The flask was transferred to an anhydrous glove box, and NiI2 (188.0 mg, 0.6 mmol, 10 mol%) was added. The flask was capped with a rubber septum and removed from the glove box. N,N-dimethylacetamide (20 mL) and pyridine (480 μL, 6.0 mmol, 100 mol%) were added using a syringe. The mixture was stirred at 25°C under a N2 atmosphere for 16 hours and then directly loaded onto a silica gel column without further treatment. The residue in the reaction vessel was rinsed with a small amount of petroleum ether. After purification by column chromatography, 4N hydrogen chloride in methanol (75 mL) was added to the effluent. The reaction was stirred at room temperature for 1 hour and filtered to obtain the desired product 1 (1.014 g, 84% yield, 98% ee).

Claims

1. A method for preparing dexmedetomidine hydrochloride 1, the synthesis steps comprising: Using 2',3'-dimethylacetophenone 2 as a raw material, a Lewis acid as a catalyst, and dimethylchlorosilane 3 as a chlorination reagent, a solvent is added and a chlorination reaction occurs at room temperature to generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4. Then, under the catalysis of a metal nickel catalyst, a ligand and an additive are added to undergo a reductive cross-coupling reaction with a 4-iodoimidazole compound 5, followed by salt formation to obtain dexmedetomidine hydrochloride compound 1. The molecular structure of 2',3'-dimethylacetophenone 2 is as follows: ； The synthetic route is shown in the following reaction formula: ； The Lewis acid is one of Fe(ClO4)3, In(OH)3, Fe(acac)3, AlCl3 or FeCl3; The solvent is ethyl acetate; The metal nickel catalyst is NiI2; The structural formula of the ligand is as follows: ； The additives are magnesium chloride, pyridine and zinc powder.

2. The method for preparing 1-(1-chloroethyl)-2,3-dimethylbenzene 4 according to claim 1, characterized in that: The molar ratio of 2',3'-dimethylacetophenone 2 to dimethylchlorosilane 3 is 1:1-1:

2.

3. The method for preparing 1-(1-chloroethyl)-2,3-dimethylbenzene 4 according to claim 1, characterized in that: The reaction time is 6-48 hours.

4. The method for preparing dexmedetomidine hydrochloride 1 according to claim 1, wherein The molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to 4-iodoimidazole compound 5 is 1:0.5-1:

1.

5. The method for preparing dexmedetomidine hydrochloride according to claim 1, wherein The molar ratio of the 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to the 4-iodoimidazole compound 5 is 1:0.5.

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