Preparation method of nortramadol hydrochloride

Abstract

The present invention belongs to the technical field of preparation of chemical drugs, and is particularly related to a method for preparing nortramadol hydrochloride. The method for preparing nortramadol hydrochloride of the present invention comprises the following steps: reacting m-bromophenol II and protective agent III in a solvent to obtain a protected product IV; adding a solution of the protected product IV and a solvent to magnesium chips and a solvent, and reacting to obtain a Grignard reagent V; reacting Grignard reagent V and 2-dimethylaminomethylcyclohexanone VI in a solvent to obtain a Grignard salt VII; adding an aqueous ammonium chloride solution to the Grignard salt VII for hydrolysis and deprotection to obtain nortramadol VIII; passing hydrogen chloride gas into an organic solvent solution of nortramadol VIII, filtering by suction, and re-refining to obtain a product, nortramadol hydrochloride. The method for preparing nortramadol hydrochloride provided by the present invention has stable process, few side reactions, strong operability, is suitable for industrial production, and the prepared nortramadol hydrochloride has high purity and high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of chemical drugs, and particularly relates to a preparation method of nortramadol hydrochloride. Background Art

[0002] Tramadol is a synthetic codeine analogue that affects pain transmission and produces analgesic effects. It has low dependence and significant antitussive and analgesic effects. The Chinese Pharmacopoeia records that the chemical name of tramadol hydrochloride is (±)-(1RS,2RS)-2-[(N,N-dimethylamino)methylene]-1-(3-methoxyphenyl)cyclohexanol hydrochloride. After demethylation, it becomes nortramadol hydrochloride, a non-morphine strong analgesic.

[0003] Patent WO03 / 048113A1: Tramadol Analogs and Uses Thereof proposes that tramadol hydrochloride is used as a raw material, and the methyl group of the substituted anisole is removed through splitting and reduction and cracking with diisobutylaluminum hydride (DIBAH) to obtain nortramadol hydrochloride (R,R configuration). The process route is as follows:

[0004] .

[0005] The above raw material tramadol hydrochloride is prepared according to the tramadol hydrochloride preparation route disclosed in CN1073085C in the prior art:

[0006] .

[0007] Based on the preparation of tramadol hydrochloride, demethylation is performed to obtain nortramadol hydrochloride. Although a high yield is achieved, the technology uses a large amount of diisobutylaluminum hydride as a reducing agent, and the amount used is as high as 3 times the molar number. In addition, diisobutylaluminum hydride is highly dangerous and expensive, which brings many disadvantages to industrialization. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a preparation method of nortramadol hydrochloride, which has stable process, few side reactions, strong operability, and is suitable for industrial production. The prepared nortramadol hydrochloride has high purity and high yield.

[0009] The preparation method of nortramadol hydrochloride of the present invention comprises the following steps:

[0010] 1) reacting m-bromophenol II with protective agent III in a solvent and an acid-binding agent, extracting and concentrating to obtain a protected product IV;

[0011] 2) After initiation, an initiator is added to the magnesium chips and the solvent, and then a solution of the protected product IV and the solvent is added to react to obtain the Grignard reagent V;

[0012] 3) reacting the Grignard reagent V with 2-dimethylaminomethylcyclohexanone VI in a solvent to obtain a Grignard salt VII;

[0013] 4) adding 20%-25% ammonium chloride aqueous solution to Grignard salt VII for hydrolysis, deprotection, extraction and concentration to obtain nortramadol VIII;

[0014] 5) Passing hydrogen chloride gas into the organic solvent solution of nortramadol VIII until the pH value is 2-3, filtering with suction, and re-purifying to obtain the product nortramadol hydrochloride.

[0015] The molar ratio of 2-dimethylaminomethylcyclohexanone VI, m-bromophenol II, protective agent III, acid binding agent, magnesium chips, and ammonium chloride is 1.0: (1.0-1.5): (1.0-1.5): (1.0-2.0): (1.0-1.5): (1.0-3.0). The structural formula of 2-dimethylaminomethylcyclohexanone VI is .

[0016] The protective agent III in step 1) is one of tert-butyldimethylchlorosilane IIIa and trimethylchlorosilane IIIb; the acid binding agent in step 1) is one of imidazole and triethylamine; and the solvent in step 1) is DMF.

[0017] The reaction temperature of step 1) is room temperature, and the reaction time is 1 h to 4 h. The 20% to 25% ammonium chloride aqueous solution refers to the mass percentage.

[0018] The solvent in step 2) and step 3) is one of 2-MeTHF and THF.

[0019] The reaction temperature of step 2) is 60°C-80°C, and the reaction time is 2h-4h.

[0020] The solvent solution of the protected product IV in step 2) is added dropwise. Before the dropwise addition, an initiator iodine particles or 1,2-dibromoethane is added to initiate the reaction, and stirring is performed during the reaction.

[0021] In step 2), the solution of the protected product IV and the solvent is prepared by first dissolving the protected product IV obtained in step 1) in a solvent 2-MeTHF or THF and then adding dropwise.

[0022] The reaction temperature of step 3) is 20°C-40°C, and the reaction time is 4h-8h.

[0023] In step 3), the 2-dimethylaminomethylcyclohexanone and the solvent are added dropwise.

[0024] The temperature of hydrolysis and deprotection in step 4) is 10°C-30°C, and the time is 30min-120min.

[0025] The organic solvent in step 5) is isopropanol or ethanol.

[0026] Specifically, the preparation method of nortramadol hydrochloride I comprises the following steps:

[0027] 1) Add m-bromophenol II and protective agent III (tert-butyldimethylsilyl chloride IIIa, trimethylsilyl chloride IIIb) to solvent DMF and acid binding agent (imidazole, triethylamine), react at room temperature for 1h-4h, extract with petroleum ether, evaporate the petroleum ether, and obtain protected product IV.

[0028] 2) Add initiator iodine particles or 1,2-dibromoethane to magnesium chips and solvent (2-MeTHF, THF) for initiation, then drop the solution of protected product IV and solvent, stir and react at 60°C-80°C for 2h-4h to obtain Grignard reagent V.

[0029] 3) Cool the Grignard reagent V, add 2-dimethylaminomethylcyclohexanone VI and a solvent dropwise therein, and react at 20°C-40°C for 4h-8h to obtain Grignard salt VII.

[0030] 4) Add 20%-25% ammonium chloride aqueous solution to Grignard salt VII, hydrolyze and deprotect at 10°C-30°C, stir for 30min-120min, extract with petroleum ether, concentrate, and evaporate the petroleum ether to obtain nortramadol VIII.

[0031] 5) Passing hydrogen chloride gas into the organic solvent isopropanol or ethanol solution of nortramadol VIII until the pH value is 2-3, filtering with suction, and re-purifying to obtain the product nortramadol hydrochloride I.

[0032] The process route for preparing nortramadol hydrochloride of the present invention is as follows: .

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] (1) The method for preparing nortramadol hydrochloride of the present invention has high purity and yield of the prepared product.

[0035] (2) The preparation method of nortramadol hydrochloride of the present invention uses meta-bromophenol instead of meta-bromoanisole in the prior art, and uses tert-butyldimethylchlorosilane IIIa and trimethylchlorosilane IIIb as protective agents to protect the hydroxyl group, has few side reactions, stable process, and is suitable for industrial production.

[0036] (3) Compared with the prior art, the preparation method of nortramadol hydrochloride of the present invention eliminates the step of reducing diisobutylaluminum hydride, and the target product is directly obtained after the Grignard reaction, which is simple to operate and has strong operability. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The HPLC spectrum of nortramadol hydrochloride prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0038] The present invention will be further described below in conjunction with specific embodiments.

[0039] The raw materials and reagents used in the following examples and comparative examples are all normal commercially available products.

[0040] Example 1

[0041] The preparation method of nortramadol hydrochloride comprises the following steps:

[0042] 1) Add 17.3 g (99%, 100 mmol) of m-bromophenol II and 15.1 g (99%, 100 mmol) of tert-butyldimethylsilyl chloride IIIa into a four-necked flask, then add 100 mL of DMF solvent and 6.8 g of imidazole (99%, 100 mmol), react at room temperature for 1 h, extract with petroleum ether, and evaporate the petroleum ether to obtain the protected product IV.

[0043] 2) Add 2.40 g (100 mmol) of magnesium chips and 10 mL of 2-MeTHF into a four-necked flask. After adding iodine particles for initiation, add dropwise the solution of protected product IV and 5 mL of 2-MeTHF. Stir the reaction at 60 °C for 4 h to obtain Grignard reagent V.

[0044] 3) The four-necked flask containing the Grignard reagent V was cooled to 20°C, 15.5 g (99%, 100 mmol) of 2-dimethylaminomethylcyclohexanone VI and 10 mL of 2-MeTHF were dropped into the four-necked flask, and the reaction was carried out at 20°C for 8 h to obtain the Grignard salt VII.

[0045] 4) Add 26.7 mL of 20% ammonium chloride (100 mmol) aqueous solution to Grignard salt VII, hydrolyze and deprotect at 10°C, stir for 120 min, extract with petroleum ether, concentrate, and evaporate the petroleum ether to obtain nortramadol VIII.

[0046] 5) Passing hydrogen chloride gas into the isopropanol solution of nortramadol VIII until the pH is 2.5, filtering, and re-purifying to obtain the product nortramadol hydrochloride I, a total of 23.3 g, HPLC purity 99.7%, and a calculated yield of 81.5%.

[0047] Example 2

[0048] The preparation method of nortramadol hydrochloride comprises the following steps:

[0049] 1) Add 26.0 g (99%, 150 mmol) of m-bromophenol II and 16.3 g (99%, 150 mmol) of trimethylsilyl chloride into a four-necked flask, then add 150 mL of DMF and 20.2 g of triethylamine (99%, 200 mmol), react at room temperature for 4 h, extract with petroleum ether, and evaporate the petroleum ether to obtain the protected product IV.

[0050] 2) Add 3.60 g (150 mmol) of magnesium chips and 15 mL of THF into a four-necked flask. After initiation with 1,2-dibromoethane, dropwise add a solution of the protected product IV and 10 mL of THF. Stir the reaction at 80 °C for 2 h to obtain the Grignard reagent V.

[0051] 3) The four-necked flask containing the Grignard reagent V was cooled to 40°C, and a solution of 15.5 g (99%, 100 mmol) of 2-dimethylaminomethylcyclohexanone VI and 10 mL of THF was dripped into the four-necked flask, and the reaction was carried out at 40°C for 4 h to obtain the Grignard salt VII.

[0052] 4) Add 64.2 mL of 25% ammonium chloride (300 mmol) aqueous solution to Grignard salt VII, hydrolyze and deprotect at 30°C, stir for 30 min, extract with petroleum ether, concentrate, and evaporate the petroleum ether to obtain nortramadol VIII.

[0053] 5) Passing hydrogen chloride gas into the ethanol solution of nortramadol VIII until the pH is 2, filtering, and re-purifying to obtain the product nortramadol hydrochloride I, a total of 24.1 g, HPLC purity 99.9%, and a calculated yield of 84.3%.

[0054] Example 3

[0055] The preparation method of nortramadol hydrochloride comprises the following steps:

[0056] 1) Add 20.8 g (99%, 120 mmol) of m-bromophenol II and 18.1 g (99%, 120 mmol) of tert-butyldimethylsilyl chloride into a four-necked flask, then add 120 mL of DMF and 10.2 g of imidazole (99%, 150 mmol), react at room temperature for 2 h, extract with petroleum ether, and evaporate the petroleum ether to obtain the protected product IV.

[0057] 2) Add 2.88 g (120 mmol) of magnesium chips and 12 mL of 2-MeTHF into a four-necked flask. After initiation by adding iodine particles as initiator, add dropwise a solution of the protected product IV and 6 mL of 2-MeTHF. Stir the reaction at 70 °C for 3 h to obtain the Grignard reagent V.

[0058] 3) The four-necked flask containing the Grignard reagent V was cooled to 30°C, and a solution of 15.5 g (99%, 100 mmol) of 2-dimethylaminomethylcyclohexanone VI and 10 mL of 2-MeTHF was dripped into the four-necked flask, and the reaction was carried out at 30°C for 6 h to obtain the Grignard salt VII.

[0059] 4) Add 32.1 mL of 25% ammonium chloride (150 mmol) aqueous solution to Grignard salt VII, hydrolyze and deprotect at 20°C, stir for 60 min, extract with petroleum ether, concentrate, and evaporate the petroleum ether to obtain nortramadol VIII.

[0060] 5) Passing hydrogen chloride gas into the isopropanol solution of nortramadol VIII until the pH is 3, filtering, and re-purifying to obtain the product nortramadol hydrochloride I, a total of 23.9 g, HPLC purity 99.7%, and a calculated yield of 83.6%.

[0061] Comparative Example 1

[0062] (1) According to the method disclosed in patent CN101265201B, a preparation step of tramadol hydrochloride is as follows:

[0063] Add 3.12 g (130 mmol) of magnesium turnings and 10 mL of 2-MeTHF to the reaction flask, add iodine pellets to initiate the reaction, add dropwise a solution of 22.3 g (120 mmol) of m-bromoanisole and 5 mL of 2-MeTHF, stir the reaction at 80 °C for 2 h, and obtain the Grignard reagent.

[0064] The mixture was cooled to 0°C, and a solution of 15.5 g (100 mmol) of 2-dimethylaminomethylcyclohexanone and 10 mL of 2-MeTHF was added dropwise into the reaction flask. The reaction was continued for 4 h. Saturated NH4Cl was added to inactivate the mixture, and 2-MeTHF was recovered under reduced pressure to obtain a tramadol concentrate.

[0065] The product was dissolved in 60 mL of isopropanol, HCl gas was introduced, and crude tramadol hydrochloride was obtained by suction filtration. The crude product was purified by adding isopropanol to obtain 25.4 g of tramadol hydrochloride with HPLC purity of 99.3% and a yield of 84.7%.

[0066] (2) According to the method disclosed in patent CN1073085C, a preparation of nortramadol hydrochloride:

[0067] Add 18.0 g (60 mmol) of tramadol hydrochloride, 90 mL of dichloromethane, 2.64 g (66 mmol) of sodium hydroxide, and 18 mL of water to the reaction flask. Stir and let stand, separate the organic layer, wash the organic layer with water, and evaporate the solvent to obtain the free base.

[0068] Add 27 mL of toluene to the free base to obtain a solution, add 120 mL of 20% diisobutylaluminum hydride (DIBAH) toluene solution dropwise at room temperature, and reflux for 11 hours.

[0069] The temperature was lowered to obtain 16.5 g of tramadol hydrochloride, with a yield of 96.2%, a HPLC purity of 99.3%, and a total yield of 84.7%×96.2%=81.5%.

[0070] The nortramadol hydrochloride prepared in the above examples and comparative examples was determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0071] Test solution: Take an appropriate amount of the product, weigh accurately, dissolve in acetic acid-sodium acetate buffer (pH 4.5)-methanol (volume ratio 65:35) and quantitatively dilute to make a solution containing about 0.5 mg per 1 mL.

[0072] Chromatographic conditions: using octadecylsilane bonded silica gel as filler (Agilent SB-C18 column, 4.6×150mm, 5μm or chromatographic column with equivalent performance); using acetic acid-sodium acetate buffer (pH4.5) as mobile phase A and methanol as mobile phase B, linear gradient elution is performed as shown in the following table; flow rate is 1.0mL per minute; detection wavelength is 271nm; injection volume is 20uL. Elution gradient is shown in Table 1.

[0073] Table 1 Elution gradient

[0074]

[0075] The system suitability requirement is that the number of theoretical plates calculated based on the main peak should be no less than 1500.

[0076] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and calculate the product yield based on the detected product purity.

[0077] Wherein, the HPLC spectrogram of the product nortramadol hydrochloride I prepared in Example 1 is as follows: Figure 1 As shown, Figure 1 The horizontal axis is time (min) and the vertical axis is voltage value (V). Figure 1 The chromatographic peak results are shown in Table 2. Figure 1 As can be seen from Table 2, at 4.680 min, the chromatographic peak of nortramadol hydrochloride I appeared.

[0078] Table 2 Chromatographic peak results

[0079]

Claims

1. A method for preparing nortramadol hydrochloride, characterized in that: The following steps are involved: 1) reacting m-bromophenol II with protective agent III in a solvent and an acid-binding agent at room temperature for 1 h to 4 h, extracting and concentrating to obtain a protected product IV; protective agent III is one of tert-butyldimethylchlorosilane and trimethylchlorosilane; The acid binding agent is one of imidazole and triethylamine; The solvent was DMF; 2) Add initiator iodine particles or 1,2-dibromoethane to magnesium chips and solvent, then drop the solution of protected product IV and solvent, stir and react at 60℃-80℃ for 2h-4h to obtain Grignard reagent V; 3) reacting the Grignard reagent V with 2-dimethylaminomethylcyclohexanone VI in a solvent to obtain a Grignard salt VII; The reaction temperature is 20°C-40°C, and the reaction time is 4h-8h; 4) adding an aqueous solution of ammonium chloride to Grignard salt VII and hydrolyzing at 10°C-30°C for 30min-120min, extracting and concentrating to obtain nortramadol VIII; 5) passing hydrogen chloride gas into the organic solvent solution of nortramadol VIII until the pH value is 2-3, filtering with suction, and re-refining to obtain the product nortramadol hydrochloride; The molar ratio of 2-dimethylaminomethylcyclohexanone VI, m-bromophenol II, protective agent III, acid binding agent, magnesium chips and ammonium chloride is 1.0: (1.0-1.5): (1.0-1.5): (1.0-2.0): (1.0-1.5): (1.0-3.0); The solvent of step 2) and the solvent of step 3) are one of 2-MeTHF and THF; The organic solvent in step 5) is one of isopropanol and ethanol; When the protective agent III is tert-butyldimethylchlorosilane, the process route for preparing nortramadol hydrochloride is as follows: 。

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