Preparation method of dexmedetomidine hydrochloride

Abstract

The invention discloses a preparation method of dexmedetomidine hydrochloride. Firstly, 2 ', 3'-dimethyl acetophenone is used as a raw material and is subjected to a chlorination reaction with dimethylchlorosilane under catalysis of Lewis acid to synthesize 1-(1-chloroethyl)-2, 3-dimethylbenzene, then under catalysis of a chiral catalyst, 1-(1-chloroethyl)-2, 3-dimethylbenzene and 4-iodoimidazole are subjected to a cross-reduction coupling reaction, and finally salifying is performed to obtain dexmedetomidine hydrochloride with the enantiomer excess percentage as high as 99%. The method has the advantages of easily available raw materials, simple operation, mild reaction conditions, short synthesis route, high yield, good stereoselectivity and the like, and has 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, general anesthesia adjuvant medication, and postoperative analgesia. The structural formula is shown below:

[0003]

[0004] At present, the methods for preparing dexmedetomidine can be mainly divided into two categories: one is the method involving the construction of an imidazole ring during the synthesis process, such as the method shown in patents WO 2013014428 A1, WO2016120635 A1, etc.; the second is the method of synthesizing from two fragments of an imidazole ring and a benzene ring, such as the method shown in patent US20100048915 A1, etc. The methods involving the construction of an imidazole ring to synthesize dexmedetomidine have the following defects: (1) it takes 3-4 steps to synthesize medetomidine, the synthesis route is too long, and the total yield of synthesizing medetomidine 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 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, CN 106083724A reported that the halogenated product of one of the aromatic fragments was used to prepare the corresponding Grignard reagent, which was added to the aromatic ketone or aldehyde of the other fragment, and then medetomidine was obtained through several steps of reaction. In this type of route for synthesizing dexmedetomidine from aromatic halogenated products and aromatic aldehydes or ketones, the Grignard reaction was used, which has strict requirements on the anhydrous operation of the process, and the reaction steps are long and the operation is relatively cumbersome. Patent CN 105254567 A discloses that N-Boc-imidazole and 1-(1-chloroethyl)-2,3-xylene are used as raw materials, titanium tetrachloride is used as Lewis acid, an alkylation reaction occurs, and medetomidine is directly synthesized in one step with a yield of 73%, and then split by tartaric acid to finally synthesize dexmedetomidine hydrochloride. When this method uses a large amount of strong Lewis acid, it is necessary to strictly control the water content in the process, especially 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 with metal rhodium salts and chiral bisphosphine ligands as catalysts. The asymmetric catalytic method greatly increases the utilization rate of raw materials, 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 asymmetric hydrogenation are expensive and the catalyst dosage is large. Patent CN108147999 A uses a catalytic amount of 0.2 mol%, but the chiral control is not good enough, and a split is required to obtain >99% ee dexmedetomidine. Patent CN 109912508 A uses a catalytic amount of 1 mol%, which is not suitable for industrial-scale production considering the cost of the catalyst.

[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, Lewis acid as a catalyst, dimethylchlorosilane 3 as a chlorination reagent, add a solvent, and generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4 under room temperature conditions. Then, under the catalysis of a chiral catalyst, a cross-reduction coupling reaction occurs with 4-iodoimidazole 5, and finally a salt is formed to obtain a hydrochloride compound 1 of dexmedetomidine.

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

[0010] On the one hand, the present invention provides a dexmedetomidine hydrochloride compound, and its molecular structure formula 1 is as follows:

[0011]

[0012] Experimental steps: 1) 2',3'-dimethylacetophenone 2 is used as raw material, Lewis acid is used as catalyst, dimethylchlorosilane 3 is used as chlorination reagent, solvent is added, and chlorination reaction occurs at room temperature to generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4 with different structures. 2) Under the catalysis of a chiral catalyst, a reduction cross-coupling reaction occurs with 4-iodoimidazole 5, 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 a conventional separation and purification method to obtain the target product. The specific reaction equation is as follows:

[0013]

[0014] Based on the above technical scheme, preferably, the catalyst is one of Fe(ClO4)3, In(OH)3, Fe(acac)3, AlCl3 or FeCl3; wherein, the reaction is best performed 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 scheme, 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 scheme, 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 of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 1 Same as above: R 1 It is hydrogen, methyl, methoxy, fluorine, chlorine, trifluoromethyl, nitro, or cyano.

[0019] Based on the above technical scheme, preferably, the catalyst is one of NiI2, NiBr2, NiSO3CF3, Ni(PPh3)2Cl2, NiCl2, Ni(COD)2, among which the reaction is best with NiI2 as the catalyst, and the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene4 to the catalyst is 1:0.01-1:0.1, preferably 1:0.1.

[0020] Based on the above technical scheme, preferably, the ligand is one of monophosphine ligands (L1-L6), diphosphine ligands (L7-L11), nitrogen phosphine ligands (L12-L13), oxazoline ligands (L14-L19), and pyridine oxazoline ligands (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 scheme, 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, and the best reaction solvent is N,N-dimethylacetamide; the reaction temperature is 0-50°C, and the best reaction temperature is 25°C; the reaction time is 6-48 hours, and the best 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 drawings required for use in the embodiments will be briefly introduced below. 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 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: 2',3'-dimethylacetophenone 2 (1.4821 g, 10.0 mmol), ferric chloride (0.0811 g, 0.5 mmol) and EtOAc (20 mL) were placed in a 50 mL single-necked round-bottom flask. 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 vigorously stirred 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 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 the product 4 compound 1.35 g, with a yield of 80%, 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 process is 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 loaded into a flame-dried Schlenk tube equipped with a stirring bar, and then 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 added. The test tube was moved into an anhydrous glove box, and NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was covered with a rubber septum and then 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 under N2 atmosphere at 25°C 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 methanol solution of hydrogen chloride (75 mL) was added to the effluent, and the reaction was stirred at room temperature for 1 hour and filtered to obtain the target product 1 (60.4 mg, yield 85%, ee value 99%).

[0031] Example 3

[0032]

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

[0034] Example 4

[0035]

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

[0037] Example 5

[0038]

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

[0040] Example 6

[0041]

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

[0043] Example 7

[0044]

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

[0046] Example 8

[0047]

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

[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 the target product 1 (53.3 mg, 75% yield, 90% ee value) was obtained after post-treatment.

[0052] Example 10

[0053]

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

[0055] Embodiment 11

[0056]

[0057] The specific process is 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 bottle equipped with a stirring bar, and then 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 added. The test tube was moved into an anhydrous glove box, and NiI2 (188.0 mg, 0.6 mmol, 10 mol%) was added. The tube was covered with a rubber septum and then 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 under N2 atmosphere at 25°C 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 methanol solution of hydrogen chloride (75 mL) was added to the effluent, and the reaction was stirred at room temperature for 1 hour and filtered to obtain the target product 1 (1.014 g, yield 84%, ee value 98%).

Claims

1. A dexmedetomidine hydrochloride compound, whose molecular structural formula 1 is as follows:

2. The method for preparing dexmedetomidine hydrochloride 1 according to claim 1, wherein the synthesis step comprises: Using 2',3'-dimethylacetophenone 2 as raw material, Lewis acid as catalyst, dimethylchlorosilane 3 as chlorination reagent, and adding solvent, a chlorination reaction occurs at room temperature to generate 1-(1-chloroethyl)-2,3-dimethylbenzene 4 with different structures, which then undergoes a reductive cross-coupling reaction with 4-iodoimidazole 5 under the catalysis of a chiral catalyst, and then forms a salt to obtain the hydrochloride compound 1 of dexmedetomidine. The molecular structure of 2',3'-dimethylacetophenone 2 is as follows: The synthetic route is shown in the following reaction formula:

3. The method for preparing 1-(1-chloroethyl)-2,3-dimethylbenzene 4 according to claim 2, characterized in that The catalyst is one of Fe(ClO4)3, In(OH)3, Fe(acac)3, AlCl3 or FeCl3, the molar ratio of 2',3'-dimethylacetophenone 2 to the catalyst is 1:0.02-1:0.1, and the molar ratio of 2',3'-dimethylacetophenone 2 to dimethylchlorosilane 3 is 1:1-1:

2.

4. The method for preparing 1-(1-chloroethyl)-2,3-dimethylbenzene 4 according to claim 3, characterized in that The solvent is one or more of 1,4-dioxane, ethyl acetate, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylformamide or tetrahydrofuran; the reaction temperature is 0-50° C.; and the reaction time is 6-48 hours.

5. The method for preparing dexmedetomidine hydrochloride 1 according to claim 2, characterized in that: The metal nickel catalyst is selected from one of NiI2, NiBr2, NiSO3CF3, Ni(PPh3)2Cl2, NiCl2, and Ni(COD)2, and the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to the catalyst is 1:0.01-1:0.1; the molar ratio of 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to 4-iodoimidazole 5 is 1:0.5-1:

1.

6. The method for preparing dexmedetomidine hydrochloride 1 according to claim 2, characterized in that The ligands include monophosphine ligands, diphosphine ligands, nitrogen phosphine ligands, oxazoline ligands, pyridine oxazoline ligands and the like.

7. The method for preparing dexmedetomidine hydrochloride 1 according to claim 2, characterized in that: The additive is one or more of magnesium chloride, pyridine and zinc powder; the solvent is one or more of 1,4-dioxane, dimethyl sulfoxide, acetonitrile, toluene, methanol, N,N-dimethylacetamide or tetrahydrofuran; the reaction temperature is 0-50° C.; and the reaction time is 6-48 hours.

8. The method for preparing dexmedetomidine hydrochloride 1 according to claim 3, characterized in that: The molar ratio of the 1-(1-chloroethyl)-2,3-dimethylbenzene 4 to 4-iodoimidazole 5 is 1:0.

5.

9. The method for preparing dexmedetomidine hydrochloride 1 according to claim 3, characterized in that: The catalyst is NiI2, and the molar ratio of o-bromostyrene 2 to NiI2 is 1:0.

1.

10. The dexmedetomidine hydrochloride compound as claimed in claim 1, used as a sedative and analgesic anesthetic in many fields such as sedation and analgesia, preoperative medication, general anesthesia adjuvant medication, and postoperative analgesia.

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