Preparation method of cyclobenzaprine hydrochloride

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of cyclobenzaprine hydrochloride. According to the preparation method disclosed by the invention, 5H-dibenzo [A, D] cycloheptatriene-5-halide is taken as an initial raw material, and after the 5H-dibenzo [A, D] cycloheptatriene-5-halide reacts with phosphite ester, the 5H-dibenzo [A, D] cycloheptatriene-5-halide further reacts with 3-(dimethylamino) propionaldehyde without separation and purification, so that cyclobenzaprine can be prepared; wherein a phosphonate intermediate compound generated after the initial raw material reacts with phosphite ester is stable in chemical property, and various side reactions can be avoided; the cyclobenzaprine can be further salified and refined through an HCl-ethyl acetate system, the whole process is simple and convenient to operate, cyclobenzaprine hydrochloride can be prepared with high yield and high purity, and the method is 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 cyclobenzaprine hydrochloride. Background Art

[0002] Cyclobenzaprine hydrochloride, chemical name 5-(3-dimethylaminopropylidene) dibenzo[a,d]cycloheptene hydrochloride, was developed by Merck in the United States and is now available in many countries under the trade name Flexeril. It is clinically used to relieve muscle spasms and the accompanying severe pain in skeletal muscles. It is also very effective for the discomfort and pain caused by other connective tissues. This product has a fast onset of action, good antispasmodic effect, and few adverse reactions. It is the first choice for the treatment of such diseases. The chemical structure is shown below:

[0003]

[0004] The currently reported synthesis methods of cyclobenzaprine hydrochloride mainly include the following:

[0005] ① Use organometallic reagents such as Grignard reagent for reaction preparation

[0006] The literature J.Org.Chem., 1962, 27(1):230-240 uses 5H-dibenzo[a,d]cycloheptatriene-5-one as the starting material, first reacts with a Grignard reagent, then removes the benzyl group and bromine with hydrogen bromide, and finally reacts with dimethylamine to obtain cyclobenzaprine. The synthetic route is as follows:

[0007]

[0008] Patents US3409640A, US3454643A and literature "Improved Synthesis Process of Cyclobenzaprine Hydrochloride", Chinese Journal of Medicinal Chemistry, 2015, 25(2): 115-117, etc., firstly react 3-(N,N-dimethylamino) chloropropane with metal magnesium to generate a Grignard reagent, then react with 5H-dibenzo[a,d]cycloheptatriene-5-one to undergo a Grignard reaction, and then dehydrate to generate cyclobenzaprine. The synthesis route is as follows:

[0009]

[0010] Patent CN111393305A first reacts 3-(N,N-dimethylamino) chloropropane with metallic zinc to obtain N,N-dimethyl-3-chlorozinc propylamine, which is then subjected to nucleophilic addition with 5H-dibenzo[a,d]cycloheptatriene-5-one to obtain 5-(3-dimethylaminopropyl)-5-hydroxydibenzocycloheptatriene, which is then dehydrated and salted to obtain cyclobenzaprine hydrochloride. The synthetic route is as follows:

[0011]

[0012] However, the above processes are all applied to organic metal halides for reaction. The related reagents are highly active and require strict control of anhydrous operation. Not only are various side reactions prone to occur and more impurities are introduced, but the operation process is also dangerous and cannot meet the requirements of industrial scale-up production.

[0013] ②Use Wittig reagent for reaction preparation

[0014] The preparation methods disclosed in the literature, such as "Study on the Synthesis of Cyclobenzaprine", Journal of Mudanjiang Medical College, 2008, 29(2):18-20, "Simple Synthesis of Cyclobenzaprine", Contemporary Medicine, 2009, 15(3):15-16, firstly, 1,3-dibromopropane is substituted with triphenylphosphine, and then replaced with dimethylamine to obtain the Wittig reagent 3-N,N-dimethyl-triphenylphosphine propylamine; and dibenzocycloheptenone is subjected to bromination reaction and elimination reaction to obtain 5H-dibenzo[a,d]cycloheptatriene-5-one; and the cyclobenzaprine is reacted with the Wittig reagent to obtain cyclobenzaprine, and then salified with hydrogen chloride gas to obtain cyclobenzaprine hydrochloride. The synthesis route is as follows:

[0015]

[0016] In patent CN102942489A, 1,3-dibromopropane is first replaced by trialkoxyphosphine, and then replaced by dimethylamine to obtain Wittig reagent; then, under nitrogen protection, cyclobenzaprine is obtained by electrochemical reaction (the working electrode and auxiliary electrode are platinum electrodes, and the reference cell is silver chloride / silver electrode) with 5H-dibenzo[a,d]cycloheptatriene-5-one, and finally the target product is obtained by hydrochloride. The synthesis route is as follows:

[0017]

[0018] However, the above-mentioned Wittig reagents all contain aliphatic hydrocarbon long-chain structural parts, which have low chemical stability and high reaction activity, and also require strict control of anhydrous conditions, which will produce various side reactions and introduce more impurities, thereby causing the problem of low reaction yield (70% to 80%). In addition, the condensation reaction needs to be carried out by electrochemical electrolysis, which has high requirements for reaction equipment and is not suitable for large-scale production applications.

[0019] ③Other methods

[0020] Indian patent 387CHE2005 uses amitriptyline as raw material, and produces cyclobenzaprine by catalytic dehydrogenation of dibutyl maleate and palladium carbon at high temperature. However, the reaction temperature of this route is relatively high (200°C), which is also difficult to meet the requirements of industrial scale-up production. The synthesis route is as follows:

[0021]

[0022] The literature Tetrahedron Lett, 51 (2010) 5690-5693 uses NaBH 4 / Raney Ni system reduces the impurities of cyclobenzaprine, namely cyclobenzaprine-N-oxide to prepare cyclobenzaprine, but the related materials are expensive and the production cost is high. The synthesis route is as follows:

[0023]

[0024] In summary, the current preparation methods of cyclobenzaprine have many deficiencies in terms of process safety, yield, production cost, etc. Therefore, it is still a problem to be solved to study and find a reaction route suitable for industrial production of cyclobenzaprine with simple operation process, high product yield, high purity and low production cost. Summary of the invention

[0025] Aiming at the problems existing in the current preparation process of cyclobenzaprine hydrochloride, the present invention provides a new preparation method of cyclobenzaprine hydrochloride, which is simple and safe to operate, has mild reaction conditions, and has high purity and yield.

[0026] The specific technical solutions of the present invention are as follows:

[0027] A method for preparing cyclobenzaprine hydrochloride, characterized in that compound I-1 is used as a starting material, first reacted with a phosphite, after the reaction is detected to be complete, alkali and 3-(dimethylamino)propanal are added to continue the reaction, and after the reaction is completed, cyclobenzaprine hydrochloride is obtained by post-treatment, and the reaction formula is as follows:

[0028]

[0029] X is one of chlorine, bromine and iodine.

[0030] A preparation method of cyclobenzaprine hydrochloride specifically comprises the following steps:

[0031] Compound I-1 is added to phosphite, and the reaction is controlled at a temperature. After the reaction is detected to be complete, an organic solvent is added, and a base and 3-(dimethylamino)propanal are added at a low temperature. The temperature is raised to react. After the reaction is detected to be complete, cyclobenzaprine hydrochloride is obtained by post-treatment.

[0032] Preferably, the phosphite is selected from one of trimethyl phosphite and triethyl phosphite, preferably triethyl phosphite.

[0033] Preferably, the organic solvent is selected from one of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran or a combination thereof, preferably N,N-dimethylformamide.

[0034] Preferably, the base is selected from sodium hydroxide, sodium methoxide and sodium ethoxide, preferably sodium methoxide.

[0035] Preferably, the molar ratio of the compound I-1 to the phosphite, the base, and the 3-(dimethylamino)propanal is 1:1.0-1.2:1.1-1.8:1.0-1.2, more preferably 1:1.0:1.5:1.0.

[0036] Preferably, the temperature of the temperature-controlled reaction is 90-110°C.

[0037] Preferably, the cryogenic temperature is -10 to 10°C, preferably 0 to 5°C.

[0038] Preferably, the temperature of the temperature-raising reaction is 10-50°C, preferably 20-25°C.

[0039] In one embodiment, the post-treatment comprises the following steps: pouring the reaction solution into water for quenching, extracting with an organic solvent, concentrating the obtained organic phase to dryness, salifying with an HCl-ethyl acetate system, filtering, and drying the filter cake to obtain cyclobenzaprine hydrochloride.

[0040] Preferably, the organic solvent for extraction is selected from one of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, preferably ethyl acetate.

[0041] Beneficial effects of the present invention:

[0042] The invention provides a novel preparation method of cyclobenzaprine hydrochloride. 5H-dibenzo[A,D]cycloheptatriene-5-halide, i.e., compound I-1, is used as a starting material. After reacting with phosphite, the starting material is directly reacted with 3-(dimethylamino)propionaldehyde through Wittig-Horner reaction without separation and purification to prepare cyclobenzaprine. The whole process is simple to operate, has fewer synthesis units, and can avoid the application of electrochemical reaction equipment, which is suitable for industrial production. The phosphonate intermediate compound prepared in the novel process has stable chemical properties, can effectively avoid the use of Grignard reagents of highly active organic metal compounds and Wittig reagents of alkyl organic phosphorus halogen compounds, and thus avoid the generation of more impurities. The cyclobenzaprine prepared in the novel process can be further refined by salt formation through an HCl-ethyl acetate system to obtain the target product cyclobenzaprine hydrochloride with high yield and purity. DETAILED DESCRIPTION

[0043] 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.

[0044] The present invention adopts HPLC to measure the purity of cyclobenzaprine hydrochloride, and the chromatographic conditions are as follows:

[0045] Chromatographic column: Octylsilane bonded silica as filler (GL Sciences Inertsil C 8-3 , 4.6mm×250mm, 5μm or chromatographic column with equivalent performance);

[0046] Mobile phase: methanol-ammonium acetate solution (5.7 g of ammonium acetate was dissolved in 1000 mL of water and the pH value was adjusted to 7.2 with 25% ammonia water) (60:40);

[0047] Column temperature: 30°C;

[0048] Detection wavelength: 240nm;

[0049] Flow rate: 1.0ml / min;

[0050] Injection volume: 20 μL;

[0051] Among them, the retention time of cyclobenzaprine is about 26 minutes.

[0052] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0053] Example 1

[0054] I-1 (X = Br, 27.16g, 0.10mol) was added to triethyl phosphite (16.62g, 0.10mol), and the temperature was controlled at 100°C for reaction. After the reaction was completed, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (10.11g, 0.10mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was completed, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 94.7% and a purity of 99.86%.

[0055] Example 2

[0056] I-1 (X = Br, 27.16g, 0.10mol) was added to triethyl phosphite (19.94g, 0.12mol), and the temperature was controlled at 100°C for reaction. After the reaction was completed, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (10.11g, 0.10mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was completed, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 94.0% and a purity of 99.49%.

[0057] Example 3

[0058] I-1 (X = Br, 27.16g, 0.10mol) was added to trimethyl phosphite (14.89g, 0.12mol), and the temperature was controlled at 100°C for reaction. After the reaction was detected to be complete, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (10.11g, 0.10mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 90.3% and a purity of 99.50%.

[0059] Example 4

[0060] I-1 (X = Br, 27.16g, 0.10mol) was added to triethyl phosphite (24.93g, 0.15mol), and the temperature was controlled at 100°C for reaction. After the reaction was detected to be complete, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (10.11g, 0.10mol) were added at -10 to -5°C, and the reaction was continued at 20 to 25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phases were concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 85.5% and a purity of 98.87%.

[0061] Example 5

[0062] I-1 (X = Br, 27.16g, 0.10mol) was added to triethyl phosphite (19.94g, 0.12mol), and the temperature was controlled at 90°C for reaction. After the reaction was detected to be complete, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (12.13g, 0.12mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 92.4% and a purity of 99.31%.

[0063] Example 6

[0064] I-1 (X = Br, 27.16 g, 0.10 mol) was added to triethyl phosphite (19.94 g, 0.12 mol), and the temperature was controlled to react at 110°C. After the reaction was detected to be complete, tetrahydrofuran (270 mL) was added, and sodium methoxide (8.10 g, 0.15 mol) and 3-(dimethylamino)propanal (9.10 g, 0.09 mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400 ml) for quenching, and extracted with ethyl acetate (800 mL×3). The organic phases were combined and washed with saturated brine (800 mL×2). The organic phases were concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70 mL), and salified with 2.0 mol / L HCl-ethyl acetate to precipitate a white solid, which was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 82.7% and a purity of 99.13%.

[0065] Example 7

[0066] I-1 (X = Br, 27.16g, 0.10mol) was added to triethyl phosphite (16.62g, 0.10mol), and the temperature was controlled at 100°C for reaction. After the reaction was detected to be complete, 1,4-dioxane (270mL) was added, and sodium hydroxide (7.20g, 0.18mol) and 3-(dimethylamino)propanal (10.11g, 0.10mol) were added at 5-10°C, and the reaction was continued at 45-50°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phases were concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 91.7% and a purity of 99.56%.

[0067] Example 8

[0068] I-1 (X = Br, 27.16 g, 0.10 mol) was added to triethyl phosphite (16.62 g, 0.10 mol), and the temperature was controlled at 100 ° C. After the reaction was completed, 1,4-dioxane (270 mL) was added, and sodium ethoxide (7.48 g, 0.11 mol) and 3-(dimethylamino) propanal (10.11 g, 0.10 mol) were added at 5-10 ° C, and the reaction was continued at 45-50 ° C. After the reaction was completed, the reaction solution was poured into water (2400 ml) to quench, extracted with ethyl acetate (800 mL×3), the organic phases were combined, washed with saturated brine (800 mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70 mL), and salified with 2.0 mol / L HCl-ethyl acetate to precipitate a white solid, which was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 90.2% and a purity of 99.39%.

[0069] Example 9

[0070] I-1 (X = I, 31.81 g, 0.10 mol) was added to triethyl phosphite (19.94 g, 0.12 mol), and the reaction was controlled at 90 ° C. After the reaction was completed, N, N-dimethylformamide (270 mL) was added, and sodium methoxide (8.10 g, 0.15 mol) and 3-(dimethylamino) propanal (12.13 g, 0.12 mol) were added at 0-5 ° C, and the reaction was continued at 20-25 ° C. After the reaction was completed, the reaction solution was poured into water (2400 ml) to quench, extracted with ethyl acetate (800 mL×3), the organic phases were combined, washed with saturated brine (800 mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70 mL), salified with 2.0 mol / L HCl-ethyl acetate, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 95.3% and a purity of 99.79%.

[0071] Example 10

[0072] I-1 (X = Cl, 22.67g, 0.10mol) was added to triethyl phosphite (19.94g, 0.12mol), and the temperature was controlled at 90°C for reaction. After the reaction was detected to be complete, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (12.13g, 0.12mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 89.8% and a purity of 99.26%.

[0073] Embodiment 11

[0074] I-1 (X = Br, 27.16g, 0.10mol) was added to triisopropyl phosphite (25.0g, 0.12mol), and the temperature was controlled at 90°C for reaction. After the reaction was detected to be complete, N,N-dimethylformamide (270mL) was added, and sodium methoxide (8.10g, 0.15mol) and 3-(dimethylamino)propanal (12.13g, 0.12mol) were added at 0-5°C, and the reaction was continued at 20-25°C. After the reaction was detected to be complete, the reaction solution was poured into water (2400ml) for quenching, and extracted with ethyl acetate (800mL×3), the organic phases were combined, and washed with saturated brine (800mL×2), and the organic phase was concentrated to dryness under reduced pressure, dissolved with a small amount of ethyl acetate (70mL), and washed with 2.0mol / L HCl-ethyl acetate formed salt, and a white solid was precipitated. The solid was filtered and dried to obtain cyclobenzaprine hydrochloride with a yield of 77.5% and a purity of 98.64%.

Claims

1. A method for preparing cyclobenzaprine hydrochloride, It is characterized in that Compound I-1 is used as a starting material, and is first reacted with a phosphite. After the reaction is detected to be complete, a base and 3-(dimethylamino)propanal are added to continue the reaction. After the reaction is completed, cyclobenzaprine hydrochloride is obtained through post-treatment. The reaction formula is as follows: X is one of chlorine, bromine and iodine.

2. The preparation method according to claim 1, It is characterized in that The specific steps include: Compound I-1 is added to phosphite, and the reaction is controlled at a temperature. After the reaction is detected to be complete, an organic solvent is added, and a base and 3-(dimethylamino)propanal are added at a low temperature. The temperature is raised to react. After the reaction is detected to be complete, cyclobenzaprine hydrochloride is obtained by post-treatment.

3. The preparation method according to claim 1 or 2, It is characterized in that The phosphite is selected from trimethyl phosphite and triethyl phosphite, preferably triethyl phosphite.

4. The preparation method according to claim 2, It is characterized in that The organic solvent is selected from one of 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran or a combination thereof.

5. The preparation method according to claim 1 or 2, It is characterized in that The alkali is selected from one of sodium hydroxide, sodium methoxide and sodium ethoxide.

6. The preparation method according to claim 1 or 2, It is characterized in that The molar ratio of the compound I-1 to the phosphite, the base and the 3-(dimethylamino)propanal is 1:1.0-1.2:1.1-1.8:1.0-1.

2.

7. The preparation method according to claim 6, It is characterized in that The molar ratio of the compound I-1 to the phosphite, the base and the 3-(dimethylamino)propanal is 1:1.0:1.5:1.

0.

8. The preparation method according to claim 2, It is characterized in that The temperature of the temperature-controlled reaction is 90-110°C.

9. The preparation method according to claim 2, It is characterized in that The low temperature is -10 to 10°C, preferably 0 to 5°C; the elevated temperature is 10 to 50°C, preferably 20 to 25°C.

10. The preparation method according to claim 1 or 2, It is characterized in that The post-treatment comprises the following steps: pouring the reaction solution into water for quenching, extracting with an organic solvent, concentrating the obtained organic phase to dryness, forming salt with an HCl-ethyl acetate system, filtering, and drying the filter cake to obtain cyclobenzaprine hydrochloride.

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