3-[3-(dimethylamino)methyl-1-cyclohexen-2-yl]phenol hydrochloride and preparation of its isomers

Abstract

The application belongs to the technical field of organic compounds, and particularly relates to a preparation method of 3-[3-(dimethylamino)methyl-1-cyclohexen-2-yl]phenol hydrochloride and isomers thereof. The preparation method comprises the following steps: heating and reacting compound III with an acid, then adding sodium hydroxide to adjust the pH value to be alkaline; then continuously adding an extractant to extract, separating to obtain a water layer, introducing carbon dioxide into the water layer, and precipitating white solids in the water layer; filtering to obtain a mixture of compound VI and compound VII; dissolving the mixture of compound VI and compound VII in a polar organic solvent, introducing hydrogen chloride gas, and performing crystallization and filtration to obtain compound I; and concentrating, filtering and recrystallizing the mother liquor to obtain compound II. The application simplifies the preparation process of tramadol analogs and integrates the process into two-step reactions; the molecular structure of tramadol hydrochloride is designed to optimize the existing problems of individual differences in analgesic effect and side effects of original tramadol and analogs.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compounds, and in particular relates to a preparation method of 3-[3-(dimethylamino)methyl-1-cyclohexene-2-yl]phenol hydrochloride and its isomers. Background Art

[0002] Opioid analgesics can inhibit the transmission of pain signals by directly binding to opioid receptors (μ, κ, and δ receptors) in the central nervous system. They are mainly used to treat moderate to severe pain such as in advanced cancer, or non-inflammatory pain conditions that are ineffective with conventional non-opioid analgesics. For example, phenylpropylamine derivatives modified from the structure of morphine, such as meperidine hydrochloride, pentazocine, and methadone, have the advantages of strong analgesic effects, rapid onset, and long duration. The preparation and research of substances with similar structures has opened up a new research field for analgesics. The structural formulas of morphine, meperidine hydrochloride, pentazocine, and methadone are as follows:

[0003] .

[0004] However, since this type of opioid analgesics acts directly on receptors in the central nervous system, producing antagonistic or agonistic effects, they are inevitably highly addictive. Some drugs (such as pentazocine) combine κ receptor agonism and partial μ receptor antagonism, which reduces the addictiveness to a certain extent, but also leads to a relatively weakened analgesic effect. The side effects of κ receptor agonism can induce mental symptoms such as hallucinations.

[0005] In recent years, research on the analgesic activity of synthetic opioids has steadily increased. Tramadol and some tramadol analogs combine a dual mechanism of weak μ receptor agonism with 5-HT and NE reuptake inhibition, maintaining analgesic efficacy while reducing dependency. However, the preparation methods of existing tramadol and its analogs still present numerous challenges.

[0006] For example, Chinese patent CN112262121A discloses a novel method for preparing tapentadol, i.e., a method for preparing a compound of formula IIa or a salt thereof from a compound of formula IIIa or a salt thereof, comprising the following steps: a) deoxygenating the compound of formula IIIa or a salt thereof in the presence of a hydrosilane reagent and an acid selected from a Lewis acid or a protic acid to provide a compound of formula IIa, wherein the compound of formula IIa is in the form of an optionally diastereomeric mixture;

[0007]

[0008] b) optionally treating the product of step a) with an acid to form an acid addition salt via the amine group and isolating the desired salt of (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine (compound of formula IIa).

[0009] The hydrosilane reagents used in this patent, such as triethylsilane and phenylsilane, have low flash points and are flammable. They are easily hydrolyzed and decomposed under acidic conditions to produce hydrogen, which increases the complexity of the operation and safety risks. In addition, the product in step a is a diastereomeric mixture with multiple configurations such as (2R, 3R) and (2S, 3S), and needs to rely on the acid addition salt in step b for separation, which will undoubtedly affect the yield of the final product IIa.

[0010] Chinese patent CN1073085C discloses a method for preparing O-desmethyltramadol enantiomers, comprising the following steps: converting a racemic tramadol salt into a base, precipitating the base with L-(+)-tartaric acid to separate the L-(+)-tartrate of the (-)-tramadol enantiomer; after releasing the base, converting the tartrate into the (-) enantiomer of O-desmethyltramadol with DIBAH; and releasing the tramadol base, reacting the (-) enantiomer of O-desmethyltramadol with DIBAH to prepare the (+)-enantiomer of O-desmethyltramadol from the mother liquor of the tartaric acid precipitation.

[0011] The preparation of tramadol enantiomers in this patent requires splitting and multiple purification steps, resulting in a time-consuming process and significant yield loss. Furthermore, diisobutylaluminum hydride (DIBAH) is a flammable and explosive strong reducing agent, requiring strict control at low temperatures and under an inert atmosphere, increasing process complexity and safety risks. Summary of the Invention

[0012] The present invention aims to provide a method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers, namely, preparing two phenylpropylamine derivative compounds. The preparation method has simple conditions, produces few by-products, and has a high yield of the final product. The method solves the problems in the preparation of tramadol and its tramadol analogs by designing the molecular structure of tramadol.

[0013] To achieve the above object, the technical solution adopted by the present invention is:

[0014] The preparation method of 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers of the present invention comprises the following steps:

[0015] (1) heating compound III and an acid to react to obtain a reaction solution;

[0016] (2) Sodium hydroxide is added to the reaction solution to adjust the pH value of the reaction solution to alkaline; then an extractant is added to extract and separate to obtain an aqueous layer, carbon dioxide is introduced into the aqueous layer, a white solid is precipitated in the aqueous layer, and a mixture of compound VI and compound VII is obtained by filtration;

[0017] (3) Dissolving the mixture of Compound VI and Compound VII in a polar organic solvent, introducing hydrogen chloride gas, crystallizing, and filtering to obtain Compound I; the mother liquor is then concentrated, filtered, and recrystallized to obtain Compound II;

[0018] The reaction equation is as follows:

[0019] .

[0020] in:

[0021] The acid is a protonic acid or a Lewis acid. The protonic acid is one or more of hydrochloric acid, sulfuric acid or hydrobromic acid. The Lewis acid is boron tribromide.

[0022] The reaction temperature is 80-100° C., and the reaction time is 12-24 hours.

[0023] The molar ratio of the compound III to the acid is 1:(0.2~1).

[0024] After adding sodium hydroxide, the pH value of the reaction solution is 10~12.

[0025] The extractant is one of dichloromethane and dichloroethane.

[0026] The end point of the carbon dioxide introduction: after the carbon dioxide is introduced, the mixture is allowed to stand until the water layer separates into an upper supernatant and a lower white solid. The supernatant is taken out and carbon dioxide is introduced. The end point is reached when the supernatant no longer becomes turbid.

[0027] The polar organic solvent is one of isopropyl alcohol and anhydrous ethanol.

[0028] The end point of introducing hydrogen chloride gas is when hydrogen chloride gas is introduced until the pH value is 2-3.

[0029] The beneficial effects of the present invention are as follows:

[0030] (1) The present invention simplifies the preparation process of tramadol analogs, thereby reducing costs and the complexity of operating conditions and improving the yield of the final product:

[0031] Tramadol analogs, such as tapentadol, typically use 1-dimethylamino-2-methyl-3-pentanone and m-bromoanisole as starting materials. The Grignard reaction is followed by chiral column separation of the target enantiomers. After hydroxyl displacement, the final product is obtained through reduction, demethylation, and salt formation. Improved synthetic methods for other tramadol analogs generally adhere to the existing synthetic strategy, employing more effective reagents for specific steps. Currently, tramadol analogs generally require multiple steps, which are prone to the production of side products (sometimes as many as 10-12 steps, and unstable intermediates). They also require the use of hazardous reagents (for example, the Grignard reaction uses ethylmagnesium bromide or ethyllithium, which requires strict anhydrous and oxygen-free conditions throughout the reaction, posing a high operational risk; the hydroxyl displacement step uses thionyl chloride, which is highly corrosive and easily decomposes to produce toxic gases such as HCl and SO₂). Chiral separation relies on chiral acids (such as L-tartaric acid) or chiral column chromatography, resulting in low yields and high costs.

[0032] The present invention directly uses tramadol hydrochloride as the basic raw material to design the molecular structure of tramadol hydrochloride, thereby optimizing the problem of large individual differences in the analgesic effects and side effects of the original tramadol and its analogs. Through acid heating reaction and acidic gas regulation, the traditional key steps of hydroxyl replacement, amination, and demethylation are integrated into a two-step reaction, reducing the number of times of generation and separation of unstable intermediates, thereby reducing the generation of by-products and losses during multiple separations, and thus improving the yield of the final product.

[0033] (2) Based on the simplified process adopted in the present invention, suitable reagents are selected to reduce production costs and improve the yield and purity of the final product:

[0034] The present invention adopts acid catalysis, that is, acid removes the methyl group of the anisole group in the mixture III, and simultaneously removes the hydroxyl group on the cyclohexane group in the form of water to form a double bond, thereby replacing the toxic, flammable and easily oxidized reagents commonly used in the synthesis of tramadol analogs, eliminating the need for complex operations such as a strict anhydrous environment or inert gas protection, simplifying the production process, and facilitating large-scale application in the process.

[0035] The present invention employs alkaline salt formation, whereby the target compound is dissolved in the aqueous layer as a sodium salt (-ONa) under alkaline conditions, while fat-soluble organic impurities are removed by dichloromethane extraction. Phase separation allows only organic solvent extraction for impurity removal, replacing column chromatography. Since the present invention does not contain highly structurally similar enantiomeric organic impurities, column chromatography separation is unnecessary, and simple extraction can meet yield requirements. Acidic gas is then introduced to protonate the sodium phenolate, generating the poorly water-soluble free phenol (-OH), allowing compounds VI and VII to precipitate as solids and subsequently be obtained by filtration. The present invention selectively precipitates the target products, namely compounds VI and VII, through phase separation, improving separation efficiency and avoiding target product loss caused by multiple purifications.

[0036] The present invention utilizes the polarity of the polar organic solvent isopropanol to separate the final products Compounds I and II with different solubilities, eliminates the problem of complex chirality control of the original products, and reduces the cost of chiral separation. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 HPLC analysis of compound I in Example 1;

[0038] Figure 2 This is the HPLC analysis spectrum of Compound II in Example 1. DETAILED DESCRIPTION

[0039] The present invention is described and illustrated in detail below with reference to the embodiments.

[0040] Example 1

[0041] 27 g of compound III and 8.5 ml of 34 wt % concentrated hydrochloric acid were added to a four-necked flask, heated to 100° C., and reacted for 12 h to obtain a reaction solution.

[0042] Sodium hydroxide was added to the reaction solution to adjust the pH to 10, followed by extraction with dichloromethane to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The end point of the carbon dioxide gas introduction was determined by standing the solution, taking out the supernatant, and introducing carbon dioxide. When the supernatant no longer became turbid, the introduction of carbon dioxide was stopped, and the mixture was filtered to obtain a mixture of compound VI and compound VII.

[0043] A mixture of compound VI and compound VII was dissolved in isopropanol, and hydrogen chloride gas was introduced to pH = 2. The mixture was crystallized, filtered, and dried to obtain 13.7 g of compound I with an HPLC purity of 99.7%. The mother liquor was then concentrated, filtered, recrystallized from isopropanol, and dried to obtain 6.0 g of compound II with an HPLC purity of 97.2%.

[0044] Compound I and Compound II were subjected to liquid chromatography analysis, respectively, and the process was as follows:

[0045] Prepare the test solution: take compound I and compound II at a mass volume fraction of 0.5 mg / mL, add acetic acid-sodium acetate buffer (pH = 4.5) and methanol mixture (the volume ratio of buffer to methanol is 65:35), and mix to obtain test solution I and test solution II.

[0046] Chromatographic conditions were set as follows: octadecylsilane bonded silica gel (Agilent SB-C18 column, 4.6 × 150 mm, 5 µm or equivalent); acetic acid-sodium acetate buffer (pH 4.5) as mobile phase A, and methanol as mobile phase B, as shown in the table below; a flow rate of 1.0 mL / min, detection wavelength of 271 nm, an injection volume of 20 µL, and a linear gradient elution. The specific process is shown in Table 1. Furthermore, the number of theoretical plates (TPs) calculated based on the peak shape parameters (retention time and peak width) of the target analyte should be at least 1500 to ensure that the chromatographic system can effectively separate the target peak from impurity peaks.

[0047]

[0048] The test solution I and the test solution II were injected into the liquid chromatograph respectively and analyzed by the liquid chromatograph. The HPLC analysis spectrum of the test solution I was as follows: Figure 1 As shown; the purity of compound I is 99.7wt%; the HPLC analysis spectrum of the test solution II is as shown Figure 2 As shown; the purity of compound II is 97.2wt%; the total yield of compound I and compound II is 80.2%.

[0049] Compound I was subjected to nuclear magnetic resonance testing, and the results were as follows: 1 H NMR (400MHz, MeOD) δ6.75 (m, 1H),

[0050] δ6.70 (m, 1H), δ7.16 (m, 1H), δ6.81 (m, 1H), δ3.20 (m, 1H), δ1.92 (m, 2H), δ1.72 (m, 2H), δ2.2 2 (m, 2H), δ6.06 (m, 1H), δ2.84 (m, overlap, 1H), δ3.20 (m, 1H), δ2.84 (s, 3H), δ2.84 (s, 3H). 13 C NMR: δ142.4, δ113.0, δ157.5, δ114.0, δ129.5, δ117.2, δ136.6, δ31.9, δ24.6, δ17.1, δ25.1, δ129.3, δ59.9, δ44.4, δ40.9. The structure obtained by NMR results was consistent with the structural formula of the target product Compound I.

[0051] Compound II was subjected to NMR testing, and the results were as follows: 1H NMR (400MHz, MeOD) δ6.74 (d, J=6.9Hz, 1H), δ6.57 (m, overlap, 1H), δ7.20 (m, 1H), δ6.57 (m, overlap, 1H), δ2. 20 (br, 2H), δ1.79 (br, overlap, 2H), δ1.79 (br, overlap, 2H), δ2.35 (br, 2H), δ3.65 (br, 2H), δ2.68 (br, 6H). 13 C NMR: δ142.9, δ114.0, δ157.6, δ114.4, δ129.7, δ118.6, δ145.3, δ122.2, δ26.7, δ21.9, δ22.2, δ32.7, δ60.3, δ41.8. The structure obtained by NMR results is consistent with the structural formula of the target product Compound II.

[0052] Example 2

[0053] 27 g of compound III and 12 ml of 30 wt % sulfuric acid were added to a four-necked flask, heated to 80° C., and reacted for 24 h to obtain a reaction solution.

[0054] Sodium hydroxide was added to the reaction solution to adjust the pH to 12, and then dichloromethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The end point of the carbon dioxide gas introduction was determined by standing the solution, taking out the supernatant, and introducing carbon dioxide. When the supernatant no longer became turbid, the introduction of carbon dioxide was stopped, and the mixture was filtered to obtain a mixture of compound VI and compound VII.

[0055] A mixture of Compound VI and Compound VII was dissolved in anhydrous ethanol and introduced with hydrogen chloride gas until the pH reached 3. The mixture was crystallized, filtered, and dried to obtain 13.1 g of Compound I. The mother liquor was further concentrated, filtered, recrystallized from isopropanol, and dried to obtain 5.7 g of Compound II. Liquid chromatography analysis was performed using the same procedures as in Example 1, revealing a purity of 99.1 wt % for Compound I and 97.0 wt % for Compound II. The combined yield of Compound I and Compound II was 76.5%.

[0056] Example 3

[0057] 27 g of compound III and 6.6 ml of 40 wt % hydrobromic acid were added to a four-necked flask, heated to 90° C., and reacted for 18 h to obtain a reaction solution.

[0058] Sodium hydroxide was added to the reaction solution to adjust the pH to 11, and then dichloromethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The end point of the carbon dioxide gas introduction was determined by standing the solution, taking out the supernatant, and introducing carbon dioxide. When the supernatant no longer became turbid, the introduction of carbon dioxide was stopped, and the mixture was filtered to obtain a mixture of compound VI and compound VII.

[0059] A mixture of Compound VI and Compound VII was dissolved in isopropanol and introduced with hydrogen chloride gas to a pH of 2. The mixture was crystallized, filtered, and dried to obtain 14.3 g of Compound I. The mother liquor was further concentrated, filtered, recrystallized from isopropanol, and dried to obtain 5.1 g of Compound II. Liquid chromatography analysis was performed using the same procedures as in Example 1, yielding a purity of 98.3 wt % for Compound I and 97.2 wt % for Compound II. The combined yield of Compound I and Compound II was 78.4%.

[0060] Example 4

[0061] A solution of 27 g of compound III, 4.5 g of boron tribromide and 50 ml of dichloroethane was added to a four-necked flask, heated to 80° C., and reacted for 12 h to obtain a reaction solution.

[0062] Sodium hydroxide was added to the reaction solution to adjust the pH to 11, followed by extraction with dichloroethane to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The end point of the carbon dioxide gas introduction was determined by standing the solution, taking out the supernatant, and introducing carbon dioxide. When the supernatant no longer became turbid, the introduction of carbon dioxide was stopped, and the mixture was filtered to obtain a mixture of compound VI and compound VII.

[0063] A mixture of Compound VI and Compound VII was dissolved in isopropanol and introduced with hydrogen chloride gas to a pH of 2. The mixture was crystallized, filtered, and dried to obtain 12.9 g of Compound I. The mother liquor was further concentrated, filtered, recrystallized from isopropanol, and dried to obtain 4.3 g of Compound I. Liquid chromatography analysis was performed using the same procedures as in Example 1, yielding a purity of 97.9 wt % for Compound I and 95.2 wt % for Compound II. The combined yield of Compound I and Compound II was 69.1%.

[0064] Comparative Example 1

[0065] The amount of hydrochloric acid was replaced with 0.85 ml of 34 wt % concentrated hydrochloric acid. The remaining raw materials and steps were the same as in Example 1, and 9.3 g of compound I was obtained with a purity of 97.1 wt %; 2.7 g of compound II was obtained with a purity of 93.0 wt %. The total yield of compound I and compound II was 47.9%.

[0066] Although the present invention has been described in detail with reference to the accompanying drawings and in conjunction with the embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those skilled in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall fall within the scope of the present invention.

Claims

1. A method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers, characterized in that: The following steps are involved: (1) heating compound III and an acid to react to obtain a reaction solution; wherein the acid is a protonic acid or a Lewis acid, the protonic acid is one or more of hydrochloric acid, sulfuric acid or hydrobromic acid, and the Lewis acid is boron tribromide; the molar ratio of compound III to the acid is 1:(0.2-1); (2) adding sodium hydroxide to the reaction solution to adjust the pH value of the reaction solution to alkaline; then adding an extractant for extraction, separating and obtaining an aqueous layer, introducing carbon dioxide into the aqueous layer, and precipitating a white solid in the aqueous layer, which is filtered to obtain a mixture of compound VI and compound VII; wherein the extractant is one of dichloromethane or dichloroethane; (3) Dissolving the mixture of Compound VI and Compound VII in a polar organic solvent, introducing hydrogen chloride gas, crystallizing, and filtering to obtain Compound I; the mother liquor is then concentrated, filtered, and recrystallized to obtain Compound II; wherein the polar organic solvent is one of isopropanol and anhydrous ethanol; The reaction equation is as follows: 。 2. The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to claim 1, characterized in that: The reaction temperature is 80~100℃.

3. The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to claim 1, characterized in that: The reaction time is 12~24h.

4. The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to claim 1, characterized in that: After adding sodium hydroxide, the pH value of the reaction solution is 10~12.

5. The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to claim 1, characterized in that: The end point of carbon dioxide introduction: After carbon dioxide is introduced, let it stand and the water layer will separate into the upper supernatant and the lower white solid. Take out the supernatant and introduce carbon dioxide. The end point is when the supernatant no longer becomes turbid.

6. The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to claim 1, characterized in that: End point of introducing hydrogen chloride gas: The end point is when hydrogen chloride gas is introduced until the pH is 2~3.

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