Preparation method of 5H-dibenzo [a, d] cycloheptatriene-5-ketone

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a cyclobenzaprine intermediate 5H-dibenzo [a, d] cycloheptatriene-5-ketone. The preparation method comprises the following steps: preparing a magnesium Grignard reagent by taking 2-(2-chlorine or bromostyrene) benzonitrile as an initial raw material, and performing intramolecular cyclization and acidification to obtain a target compound I; the whole process is moderate in reaction temperature and mild in condition, use of expensive catalysts and special production equipment is avoided, and the production cost can be effectively reduced; meanwhile, the use of carbon tetrachloride and bromine with higher toxicity is avoided, the operation is safe, and the method is more suitable for industrial application.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a cyclobenzaprine intermediate 5H-dibenzo[a,d]cycloheptatriene-5-one. Background Art

[0002] Cyclobenzaprine hydrochloride, chemical name 5-(3-dimethylaminopropylidene) dibenzo[a,d]cycloheptene hydrochloride, trade name Flexeril, is a centrally acting muscle relaxant developed by Merck, USA. It is clinically used to relieve muscle spasms and the accompanying severe pain in skeletal muscles, and is also very effective for the discomfort and pain caused by other connective tissues. The chemical structure of cyclobenzaprine hydrochloride is as follows:

[0003]

[0004] There are many patents and literatures reporting the preparation process of cyclobenzaprine hydrochloride, such as patents US3454643A, WO2012098563A2, CN102942489A, CN103242170B and literatures Acta.Chemical Scandinavica, 17 (1963) 2437-2443, Journal of Medicinal and Pharmaceutical Chemistry, 1962, 5, 2, 373-383, Synthesis of cyclobenzaprine, Journal of Mudanjiang Medical College, 2008, 29(2), 18-20, Synthesis of cyclobenzaprine hydrochloride, Chinese Journal of Pharmaceutical Industry, 2008, 39(8), 569-570, Simple synthesis of cyclobenzaprine, Contemporary Medicine, 2009, 15(3), 15-16, Improvement of the synthesis process of cyclobenzaprine hydrochloride, Chinese Journal of Medicinal Chemistry, 2015, 25(2), 115-117, etc.

[0005] Among them, 5H-dibenzo[a,d]cycloheptatriene-5-one is a key intermediate in the synthesis of cyclobenzaprine hydrochloride, which can directly affect the production, market supply and quality of the drug. Its chemical structure is as follows:

[0006]

[0007] The intermediate can also be used as a key material for the synthesis of the antidepressant drug Amitriptyline hydrochloride and its metabolite Nortriptyline. The chemical structure of Amitriptyline hydrochloride and its metabolite Nortriptyline is as follows:

[0008]

[0009] The currently reported preparation method of 5H-dibenzo[a,d]cycloheptatriene-5-one is as follows:

[0010] Synthesis of cyclobenzaprine, Journal of Mudanjiang Medical College, 2008, 29(2), Simple synthesis of cyclobenzaprine, Contemporary Medicine, 2009, 15(3), 15-16 reported that dibenzo[a,d]cycloheptan-5-one was used as the starting material, bromine was brominated in carbon tetrachloride and refluxed for 18 hours, then triethylamine was added and refluxed for 16 hours, and then the target product was obtained by post-treatment. However, this reaction requires the use of carbon tetrachloride and bromine, which are highly toxic, and the operation safety is low; the preparation reaction cycle is also long, which is not suitable for industrial scale-up. The synthesis route is as follows:

[0011]

[0012] In the document ACS Catal. 2014, 4, 11, 4034-4039, the target product was obtained by using the trans-dibromo compound as the substrate under the protection of argon gas and the action of α-selenothiophene and tetramethylethylenediamine through a Schlenk tube device under light radiation. However, the relevant substrate still needs to be prepared by substitution with bromine, which is more toxic, and the organic selenium catalyst is not easy to obtain. The preparation of the target product is at the milligram level and requires column chromatography purification, which is difficult to mass produce.

[0013] The literature Bull. Korean Chem. Soc. 34 (2013) 7, 1951-1952 uses NbCl 5 The / In system selectively debrominates vic-dibromide to olefins, but the catalyst cost is relatively high. The synthesis route is as follows:

[0014]

[0015] Reference ACS Catal. 2018, 8, 4, 3030-3034 uses an alcohol oxidation strategy to prepare the target product. The reaction needs to be carried out at 90°C for 48 hours under a carbon dioxide environment and needs to be carried out in a strictly anhydrous glove box. The reaction cycle is relatively long and the target product also needs to be purified by column chromatography, making it difficult to mass produce.

[0016] The document Tetrahedron Letters, 55 (2014) 6895-6898 adopts Swern-type oxidation preparation. The reaction not only needs to be carried out at -30°C, which has high requirements on equipment, but also easily produces odorous dimethyl sulfide toxic gas after the reaction. At the same time, the preparation is at the millimole level, which is difficult to mass produce. The synthesis route is as follows:

[0017]

[0018] Patent CN113929566A uses 3-(2-benzoylphenyl) acrylic acid as the starting material, and produces the target product by intramolecular decarboxylation coupling under microwave conditions with the action of a silver catalyst and an oxidant. However, the reaction needs to be carried out under microwave conditions, which places additional high requirements on the reaction device. The synthetic route is as follows:

[0019]

[0020] Patent CN202111331572.4 uses methyl 2-vinylbenzoate as the starting material, reacts with elemental sulfur under the action of trimethylaluminum to obtain methyl 2-vinylthiobenzoate, and then reacts with (2-bromophenyl)boric acid under the action of cuprous thiophene-2-carboxylate (CuTC) and palladium catalyst to obtain (2-bromophenyl) (2-vinylphenyl) ketone through Liebeskind coupling reaction, and finally obtains the target product through intramolecular Heck coupling reaction cyclization, but this process requires the use of a variety of metal catalysts or reagents, which not only has a high production cost, but also causes the problem of excessive metal residues in the target product. The synthesis route is as follows:

[0021]

[0022] In summary, the current preparation methods of 5H-dibenzo[a,d]cycloheptatriene-5-one have many shortcomings, such as poor process safety, cumbersome operation, low yield, high production cost, etc. Therefore, it is still a problem to be solved to study and find a reaction route for 5H-dibenzo[a,d]cycloheptatriene-5-one with simple operation process, high product yield, high purity and low production cost. Summary of the invention

[0023] Aiming at the problems existing in the current 5H-dibenzo[a,d]cycloheptatriene-5-one preparation technology, the present invention provides a novel preparation method of 5H-dibenzo[a,d]cycloheptatriene-5-one. The method is simple and safe to operate, has mild reaction conditions, and the obtained target product has high purity and yield.

[0024] The specific technical solutions of the present invention are as follows:

[0025] A method for preparing 5H-dibenzo[a,d]cycloheptatriene-5-one, characterized in that SM is used as a starting material, first reacted with magnesium to prepare a Grignard reagent, then cyclized under the action of a catalyst, and finally acidified to obtain compound I; the reaction formula is as follows:

[0026]

[0027] Preferably, a method for preparing 5H-dibenzo[a,d]cycloheptatriene-5-one comprises the following operations:

[0028] Under inert gas protection, magnesium is added to a dry organic solvent at a certain temperature, stirred, and a solution of SM in a dry organic solvent is slowly added dropwise. After the addition is completed, the reaction is continued with stirring for 1 to 2 hours. A catalyst is added and the temperature is raised to react. After the reaction is completed, acid is added at room temperature to adjust the pH to ≤ 2, and the reaction is continued. After the reaction is completed, compound I is obtained by detection.

[0029] Preferably, X in the SM is one of chlorine and bromine, preferably bromine.

[0030] Preferably, the organic solvent is one of tetrahydrofuran and 2-methyltetrahydrofuran, preferably tetrahydrofuran.

[0031] Preferably, the magnesium is new magnesium powder or magnesium chips, preferably freshly shaved magnesium chips, which can also be used directly after removing the oxide layer with dilute acid.

[0032] Preferably, the catalyst is cuprous bromide, cuprous iodide or a combination thereof, preferably cuprous bromide.

[0033] Preferably, the molar ratio of SM to magnesium and catalyst is 1:1.05-1.3:0.03-0.08, preferably 1:1.1:0.05.

[0034] The acid is selected from hydrochloric acid, sulfuric acid and phosphoric acid.

[0035] Preferably, the certain temperature is 0-15°C, preferably 5-10°C; the temperature of the temperature-raising reaction is 30-60°C, preferably 40-45°C.

[0036] The inert gas is one of argon and nitrogen.

[0037] In one embodiment, after the reaction is completed, post-treatment is required, and the post-treatment comprises the following steps: adding an appropriate amount of water to the reaction solution, extracting with an organic solvent, combining the organic phases, washing the organic phases with saturated brine, and concentrating to dryness to obtain compound I.

[0038] Preferably, the organic solvent for extraction is selected from the group consisting of dichloromethane, chloroform and methyl tert-butyl ether, preferably dichloromethane.

[0039] In one embodiment, a small amount of iodine may be added during the reaction or the Grignard reaction may be initiated by heating.

[0040] Beneficial effects of the present invention:

[0041] The present invention provides a novel method for preparing 5H-dibenzo[a,d]cycloheptatriene-5-one, using SM as a starting material, first preparing a Grignard reagent, then heating up for intramolecular cyclization, and finally acidifying to obtain a target compound I. The novel process is simple to operate, has a moderate reaction temperature, and mild reaction conditions, and can effectively avoid the use of ultra-low temperature equipment and microwave or light irradiation equipment, thereby reducing production costs. The novel process can avoid the use of highly toxic carbon tetrachloride and bromine, and the operation is safer. The novel process can effectively avoid the use of expensive catalysts, and the prepared 5H-dibenzo[a,d]cycloheptatriene-5-one has a high yield and purity, and is suitable for industrial production. DETAILED DESCRIPTION

[0042] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention all fall within the scope of protection claimed by the present invention.

[0043] The present invention adopts HPLC to measure the purity of 5H-dibenzo[a,d]cycloheptatriene-5-one, and the chromatographic conditions are as follows:

[0044] Chromatographic column: Hypersil BDS-C 18 Column (4.6mm×250mm, 5μm) or chromatographic column with equivalent performance;

[0045] Mobile phase: acetonitrile-0.085% phosphoric acid aqueous solution (triethylamine adjusted pH to 6.5) (65:35)

[0046] Column temperature: 30°C;

[0047] Detection wavelength: 210nm;

[0048] Flow rate: 1.0ml / min;

[0049] Injection volume: 20 μl;

[0050] Among them, the retention time of 5H-dibenzo[a,d]cycloheptatriene-5-one is about 41.913min.

[0051] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0052] Example 1

[0053] Under argon protection, the temperature was controlled at 5-10°C, and freshly shaved magnesium chips (2.67 g, 0.11 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h, and cuprous bromide (0.72 g, 0.005 mol) was added. The temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute hydrochloric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 96.9% and a purity of 99.15%.

[0054] Example 2

[0055] Under argon protection, the temperature was controlled at 5-10°C, freshly shaved magnesium chips (2.67 g, 0.11 mol) and a small particle of iodine were added to redistilled tetrahydrofuran (30 ml), stirred and mixed, and then a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h, and cuprous bromide (0.72 g, 0.005 mol) was added. The temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute hydrochloric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml×3). The organic phases were combined, washed with saturated brine (50 ml×2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 98.4% and a purity of 99.12%.

[0056] Example 3

[0057] Under argon protection, the temperature was controlled at 5-10°C, and freshly shaved magnesium chips (3.15 g, 0.13 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h. Cuprous bromide (0.72 g, 0.005 mol) was added, and the temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 95.5% and a purity of 99.03%.

[0058] Example 4

[0059] Under argon protection, the temperature was controlled at 5-10°C, and freshly shaved magnesium chips (3.15 g, 0.13 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h, and cuprous bromide (1.15 g, 0.008 mol) was added. The temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 95.0% and a purity of 98.94%.

[0060] Example 5

[0061] Under argon protection, the temperature was controlled at 5-10°C, and freshly shaved magnesium chips (2.55 g, 0.105 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h, and cuprous bromide (0.72 g, 0.005 mol) was added. The temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 92.7% and a purity of 98.79%.

[0062] Example 6

[0063] Under argon protection, the temperature was controlled at 0-5°C, and freshly shaved magnesium chips (2.55 g, 0.105 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h. Cuprous bromide (0.43 g, 0.003 mol) was added, and the temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 90.5% and a purity of 98.70%.

[0064] Example 7

[0065] Under argon protection, the temperature was controlled at 5-10°C, and freshly shaved magnesium chips (3.15 g, 0.13 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h. Cuprous bromide (1.43 g, 0.003 mol) was added, and the temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 85.6% and a purity of 98.55%.

[0066] Example 8

[0067] Under argon protection, the temperature was controlled at 0-5°C, and freshly shaved magnesium chips (2.55 g, 0.105 mol) were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Br, 28.42 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 1 h. Cuprous bromide (0.14 g, 0.001 mol) was added, and the temperature was raised to 40-45°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 80.2% and a purity of 98.47%.

[0068] Example 9

[0069] Under argon protection, the temperature was controlled at 0-5°C, freshly shaved magnesium chips (2.67 g, 0.11 mol) and a small grain of iodine were added to redistilled tetrahydrofuran (30 ml), stirred and mixed, and then a solution of SM-1 (X = Cl, 23.97 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 2 h, and cuprous bromide (0.72 g, 0.005 mol) was added. The temperature was raised to 30-35°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 96.4% and a purity of 99.08%.

[0070] Example 10

[0071] Under argon protection, the temperature was controlled at 10-15°C, and freshly shaved magnesium chips (2.67 g, 0.11 mol) and a small grain of iodine were added to redistilled tetrahydrofuran (30 ml). After stirring and mixing, a solution of SM-1 (X = Cl, 23.97 g, 0.1 mol) in dry tetrahydrofuran (60 ml) was slowly added dropwise. After the addition was complete, the reaction was continued with stirring for 2 h, and cuprous iodide (0.95 g, 0.005 mol) was added. The temperature was raised to 55-60°C for reaction. After the reaction was completed, dilute sulfuric acid was added at room temperature to adjust the pH to 2, and the reaction was continued with stirring. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 ml × 3). The organic phases were combined, washed with saturated brine (50 ml × 2), and concentrated to dryness under reduced pressure to obtain Compound I with a yield of 93.3% and a purity of 99.01%.

Claims

1. A method for preparing 5H-dibenzo[a,d]cycloheptatriene-5-one, It is characterized in that Using SM as the starting material, it first reacts with magnesium to prepare a Grignard reagent, then forms a ring under the action of a catalyst, and finally acidifies to obtain compound I; the reaction formula is as follows: Wherein X is one of chlorine and bromine.

2. The preparation method according to claim 1, It is characterized in that The method comprises the following operations: adding magnesium to a dry organic solvent at a certain temperature under inert gas protection, stirring, slowly dropping a solution of SM in a dry organic solvent, and after the dropping is completed, continuing to stir and react for 1 to 2 hours, adding a catalyst, heating the reaction, and after the reaction is completed, adding acid at room temperature to adjust the pH to ≤2, continuing the reaction, and obtaining compound I after the reaction is completed through detection.

3. The preparation method according to claim 1, It is characterized in that In the SM, X is bromine.

4. The preparation method according to claim 2, It is characterized in that The organic solvent is one of tetrahydrofuran and 2-methyltetrahydrofuran.

5. The preparation method according to claim 1 or 2, It is characterized in that The catalyst is cuprous bromide, cuprous iodide or a combination thereof.

6. The preparation method according to claim 1 or 2, It is characterized in that The feeding molar ratio of SM to magnesium and catalyst is 1:1.05-1.3:0.03-0.

08.

7. The preparation method according to claim 6, It is characterized in that The feeding molar ratio of SM to magnesium and catalyst is 1:1.1:0.

05.

8. The preparation method according to claim 2, It is characterized in that The certain temperature is 0-15°C, preferably 5-10°C.

9. The preparation method according to claim 2, It is characterized in that The temperature of the temperature-raising reaction is 30-60°C, preferably 40-45°C.

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