Preparation method of 3-[3-(dimethylamino) methyl-1-cyclohexene-2-yl] phenol hydrochloride and isomeride of 3-[3-(dimethylamino) methyl-1-cyclohexene-2-yl] phenol hydrochloride

Abstract

The invention belongs to the technical field of organic compounds, and particularly relates to a preparation method of 3-[3-(dimethylamino) methyl-1-cyclohexene-2-yl] phenol hydrochloride and an isomer thereof. The preparation method comprises the following steps: carrying out heating reaction on a compound III and acid, then adding sodium hydroxide, and adjusting the pH value to be alkaline; continuously adding an extracting agent for extraction, separating to obtain a water layer, introducing carbon dioxide into the water layer, separating out a white solid from the water layer, and filtering to obtain a mixture of a compound VI and a compound VII; dissolving the mixture of the compound VI and the compound VII in a polar organic solvent, introducing hydrogen chloride gas, crystallizing and filtering to obtain a compound I; and carrying out concentration, filtration and recrystallization on the mother liquor to obtain a compound II. The preparation process of the tramadol analogue is simplified and is integrated into two-step reaction; the molecular structure of tramadol hydrochloride is designed, and the problem that the individual differences of the analgesic effect and side effect of the original tramadol and analogues are large is solved.

Description

Technical Field

[0001] The present invention 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 its isomers. Background Art

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

[0003] However, since such opioid analgesics directly act on receptors in the central nervous system, producing antagonistic or agonistic effects, they inevitably have a high addiction potential; some drugs (such as pentazocine) combine κ-receptor agonism and partial μ-receptor antagonism, which although reducing the addiction potential to a certain extent, also lead to a relatively weakened analgesic effect and the side effects of κ-receptor agonism can induce mental symptoms such as hallucinations.

[0004] In recent years, the research on the analgesic activity of synthetic opioids has gradually increased. Among them, tramadol and some tramadol analogs combine the dual mechanisms of weak μ-receptor agonism and reuptake inhibition of 5-HT and NE, etc., which not only retain the analgesic effect but also reduce dependence. However, there are still many problems in the preparation methods of existing tramadol and its analogs.

[0005] For example, Chinese Patent CN112262121A discloses a new method for preparing tapentadol, that is, a method for preparing a compound of formula IIa or its salt from a compound of formula IIIa or its salt, which includes the following steps: a) deoxygenating the compound of formula IIIa or its salt in the presence of a hydrosilane reagent and an acid selected from Lewis acids or proton acids to provide a compound of formula IIa, and the compound of formula IIa is in the form of an optionally diastereomeric mixture;

[0006] b) Optionally treating the product in step a) with an acid to form an acid addition salt via the amino group, and separating the salt of the desired (2R,3R)-[3-(3-methoxyphenyl)-2-methyl-pentyl]dimethylamine (compound of formula IIa).

[0007] The hydrosilane reagents used in this patent, such as triethylsilane and phenylsilane, have low flash points and are flammable. They are prone to hydrolysis and decomposition to produce hydrogen under acidic conditions, increasing the operational complexity and safety risks. Additionally, the product in step a is a diastereomeric mixture, with multiple configurations such as (2R,3R) and (2S,3S), and separation relies on the acid addition salts in step b, which will undoubtedly affect the yield of the final product IIa.

[0008] Chinese Patent CN1073085C discloses a method for preparing O-demethyltramadol enantiomers, including the following steps: converting the racemic tramadol salt into a base, performing precipitation treatment with L-(+)-tartaric acid to separate the L-(+)-tartrate salt of the (-)-tramadol enantiomer, after releasing the base, converting the tartrate salt into the (-)-enantiomer of O-demethyltramadol with DIBAH, and then reacting the (-)-enantiomer of O-demethyltramadol with DIBAH by releasing tramadol base to prepare the (+)-enantiomer of O-demethyltramadol from the mother liquor of the tartaric acid precipitation.

[0009] When preparing tramadol enantiomers in this patent, it is necessary to go through separation and multiple purification steps, resulting in a time-consuming process and a large loss in yield. Additionally, diisobutylaluminum hydride (DIBAH) is a highly flammable and explosive strong reducing agent, and strict control in a low-temperature and inert gas environment is required during operation, increasing the process complexity and safety risks. Summary of the Invention

[0010] The purpose of the present invention is to provide a method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers, that is, to prepare two phenylpropylamine derivative compounds. The preparation method has simple conditions, few by-products, and a high yield of the final product; by designing the molecular structure of tramadol, the problems in the preparation methods of tramadol and its analogs are solved.

[0011] To achieve the above purpose, the technical solution adopted by the present invention is: The method for preparing 3-[3-[(dimethylamino)methyl]-1-cyclohexen-2-yl]phenol hydrochloride and its isomers according to the present invention includes the following steps: (1) Heating and reacting compound III with an acid to obtain a reaction solution; (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 to obtain an aqueous layer, introducing carbon dioxide into the aqueous layer, a white solid precipitates in the aqueous layer, and filtering to obtain a mixture of compound VI and compound VII; (3) Dissolve the mixture of compound VI and compound VII in a polar organic solvent, introduce hydrogen chloride gas, crystallize and filter to obtain compound I; the mother liquor is then concentrated, filtered and recrystallized to obtain compound II; The reaction equation is as follows: .

[0012] 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.

[0013] The reaction temperature is 80-100 °C and the reaction time is 12-24 h.

[0014] The molar ratio of compound III to the acid is 1:(0.2-1).

[0015] After adding sodium hydroxide, the pH value of the reaction solution is 10-12.

[0016] The extraction agent is one of dichloromethane or dichloroethane.

[0017] The end point of introducing carbon dioxide: After introducing carbon dioxide, let it stand. The aqueous layer is divided 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.

[0018] The polar organic solvent is one of isopropanol or absolute ethanol.

[0019] The end point of introducing hydrogen chloride gas: The end point is when the pH = 2-3 after introducing hydrogen chloride gas until the pH reaches 2-3.

[0020] The beneficial effects of the present invention are as follows: (1) The present invention simplifies the preparation process of tramadol analogs, thereby reducing costs and the complexity of operating conditions and increasing the yield of the final product: For tramadol analogs, such as tapentadol, in the prior art, 1-dimethylamino-2-methyl-3-pentanone and m-bromoanisole are mostly used as starting materials. After a Grignard reaction, the target enantiomer is separated by a chiral column, followed by hydroxyl group substitution, reduction, demethylation reaction and salification to obtain the final product. The improvement of the synthesis methods of other tramadol analogs basically remains on the existing synthesis idea, that is, more effective reagents are selected for a certain step. Currently, most tramadol analogs basically have multiple steps of reactions, are prone to produce by-products (sometimes up to 10-12 steps, and the intermediates are unstable); dangerous reagents need to be used (for example, ethylmagnesium bromide or ethyllithium is used in the Grignard reaction, and the whole process of the reaction operation requires strict anhydrous and anaerobic conditions, with high operation risks; and for example, thionyl chloride is used in the hydroxyl group substitution process, which is highly corrosive and easily decomposes to produce HCl, SO 2toxic gases such as); chiral separation relies on chiral acids (such as L-tartaric acid) or chiral column chromatography, with problems such as low yield and high cost.

[0021] In the present invention, by directly using tramadol hydrochloride as the basic raw material and designing the molecular structure of tramadol hydrochloride, the problem of large individual differences in analgesic effects and side effects existing in the original tramadol and its analogs is optimized. Through acid heating reaction and acidic gas regulation, the traditional key steps such as hydroxyl substitution, amination, and demethylation are integrated into two-step reactions, reducing the generation and separation times of unstable intermediates, thereby reducing the generation of by-products and losses during multiple separations, and thus improving the yield of the final product.

[0022] (2) On the basis of the simplified process adopted in the present invention, appropriate reagents are further selected to reduce production costs and improve the yield and purity of the final product: The present invention uses acid catalysis, that is, the acid removes the methyl group in the anisole group of mixture III, and at the same time removes the hydroxyl group on the cyclohexyl group in the form of water to form a double bond, thus replacing the toxic, flammable, and easily oxidizable reagents commonly used in the synthesis of tramadol analogs. There is no need for complex operations such as a strictly anhydrous environment or inert gas protection, simplifying the production process and facilitating large-scale application in the process.

[0023] The present invention uses base to form salts, that is, under alkaline conditions, the target compound is dissolved in the aqueous layer in the form of sodium salt (-ONa), while the fat-soluble organic impurities are extracted and removed by dichloromethane; through the phase separation method, only organic solvent extraction for impurity removal is required, replacing column chromatography. Since there are no enantiomeric organic impurities with highly similar structures in the present invention, column chromatography separation is not required, and simple extraction can meet the yield requirements. Then, acidic gas is introduced to protonate the phenolate to generate free phenol (-OH) that is insoluble in water, so that compounds VI and VII can precipitate in solid form and then be obtained by filtration. The present invention selectively precipitates the target products, namely compounds VI and VII, through the phase separation method, improving the separation efficiency and avoiding the loss of the target product caused by multiple purifications.

[0024] The present invention utilizes the polar characteristics of the polar organic solvent isopropanol to separate the final products, compounds I and II, with different solubilities, eliminating the problem of complex original product chiral control and reducing the chiral resolution cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is the HPLC analysis chromatogram of compound I in Example 1; Figure 2 It is the HPLC analysis chromatogram of compound II in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention will be specifically described and illustrated below in conjunction with the examples.

[0027] Example 1 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.

[0028] Sodium hydroxide was added to the reaction solution to adjust the pH to 10, and then dichloromethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. Judgment of the end point of carbon dioxide gas introduction: The supernatant was taken out by standing, carbon dioxide was introduced, and when the supernatant no longer became turbid, the introduction of carbon dioxide was stopped, and a mixture of Compound VI and Compound VII was obtained by filtration.

[0029] The mixture of Compound VI and Compound VII was dissolved in isopropanol, hydrogen chloride gas was introduced until the pH reached 2, crystallization, filtration and drying were carried out to obtain 13.7 g of Compound I with an HPLC purity of 99.7%. The mother liquor was concentrated, filtered, recrystallized in isopropanol and dried to obtain 6.0 g of Compound II with an HPLC purity of 97.2%.

[0030] Liquid chromatography analysis was carried out on Compound I and Compound II respectively, and the process was as follows: Preparation of test solution: According to the mass-volume fraction of 0.5 mg / mL, Compound I and Compound II were respectively taken, and after adding a mixture of acetic acid-sodium acetate buffer solution (pH = 4.5) and methanol (the volume ratio of the buffer solution to methanol was 65:35), they were mixed evenly to obtain Test Solution I and Test Solution II.

[0031] Chromatographic conditions were set: Octadecylsilane chemically bonded silica gel was used as the filler (Agilent SB-C18 column, 4.6×150 mm, 5 µm or a chromatographic column with equivalent efficiency); acetic acid-sodium acetate buffer solution (pH = 4.5) was used as mobile phase A, and methanol was used as mobile phase B, and carried out according to the following table; the flow rate was 1.0 ml per minute, the detection wavelength was 271 nm, the injection volume was 20 µL, and linear gradient elution was adopted. The specific process is shown in Table 1. In addition, the number of theoretical plates was calculated based on the peak shape parameters (retention time and peak width) of the target analyte, and the number of theoretical plates was not less than 1500 to ensure that the chromatographic system could effectively separate the target peak from the impurity peaks.

[0032]

[0033] Test Solution I and Test Solution II were respectively injected into the liquid chromatograph for analysis using the liquid chromatograph. The HPLC analysis chromatogram of Test Solution I is as Figure 1 shown; the purity of Compound I was 99.7 wt%; the HPLC analysis chromatogram of Test Solution II is as Figure 2As shown; the purity of Compound II is 97.2 wt%; the total yield of Compound I and Compound II is 80.2%.

[0034] The nuclear magnetic resonance (NMR) test was carried out on Compound I, and the results are as follows: 1 H NMR (400 MHz, MeOD) δ 6.75 (m, 1H), δ 6.70 (m, 1H), δ 7.16 (m, 1H), δ 6.81 (m, 1H), δ 3.20 (m, 1H), δ 1.92 (m, 2H), δ 1.72 (m, 2H), δ 2.22 (m, 2H), δ 6.06 (m, 1H), δ 2.84 (m, overlap, 1H), δ 3.20 (m, 1H), δ 2.84 (s, 3H), δ 2.84 (s, 3H). 13 C NMR: δ 142.4, δ 113.0, δ 157.5, δ 114.0, δ 129.5, δ 117.2, δ 136.6, δ 31.9, δ 24.6, δ 17.1, δ 25.1, δ 129.3, δ 59.9, δ 44.4, δ 40.9. The structure obtained from the NMR results is consistent with the structural formula of the target product Compound I.

[0035] The nuclear magnetic resonance (NMR) test was carried out on Compound II, and the results are as follows: 1 H NMR (400 MHz, MeOD) δ 6.74 (d, J = 6.9 Hz, 1H), δ 6.57 (m, overlap, 1H), δ 7.20 (m, 1H), δ 6.57 (m, overlap, 1H), δ 2.20 (br, 2H), δ 1.79 (br, overlap, 2H), δ 1.79 (br, overlap, 2H), δ 2.35 (br, 2H), δ 3.65 (br, 2H), δ 2.68 (br, 6H). 13 C NMR: δ 142.9, δ 114.0, δ 157.6, δ 114.4, δ 129.7, δ 118.6, δ 145.3, δ 122.2, δ 26.7, δ 21.9, δ 22.2, δ 32.7, δ 60.3, δ 41.8. The structure obtained from the NMR results is consistent with the structural formula of the target product Compound II.

[0036] Example 2 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.

[0037] Sodium hydroxide was added to the reaction solution to adjust the pH to 12. Then dichloromethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The judgment of the end point of carbon dioxide gas introduction: The supernatant was taken out by standing, carbon dioxide was introduced, and when the supernatant no longer became turbid, the introduction of carbon dioxide was stopped. The mixture of compound VI and compound VII was obtained by filtration.

[0038] The mixture of compound VI and compound VII was dissolved in absolute ethanol, and hydrogen chloride gas was introduced until the pH reached 3. Crystals were precipitated, filtered, and dried to obtain 13.1 g of compound I. The mother liquor was concentrated, filtered, recrystallized in isopropanol, and then dried to obtain 5.7 g of compound II. The liquid chromatography analysis procedure was the same as that in Example 1. It was found that the purity of compound I was 99.1 wt% and the purity of compound II was 97.0 wt%. The total yield of compound I and compound II was 76.5%.

[0039] Example 3 27 g of compound III and 6.6 ml of 40 wt% hydrobromic acid were added to a four-necked flask and heated to 90 °C for 18 h to obtain a reaction solution.

[0040] Sodium hydroxide was added to the reaction solution to adjust the pH to 11. Then dichloromethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The judgment of the end point of carbon dioxide gas introduction: The supernatant was taken out by standing, carbon dioxide was introduced, and when the supernatant no longer became turbid, the introduction of carbon dioxide was stopped. The mixture of compound VI and compound VII was obtained by filtration.

[0041] The mixture of compound VI and compound VII was dissolved in isopropanol, and hydrogen chloride gas was introduced until the pH reached 2. Crystals were precipitated, filtered, and dried to obtain 14.3 g of compound I. The mother liquor was concentrated, filtered, recrystallized in isopropanol, and then dried to obtain 5.1 g of compound II. The liquid chromatography analysis procedure was the same as that in Example 1. It was found that the purity of compound I was 98.3 wt% and the purity of compound II was 97.2 wt%. The total yield of compound I and compound II was 78.4%.

[0042] Example 4 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 and heated to 80 °C for 12 h to obtain a reaction solution.

[0043] Sodium hydroxide was added to the reaction solution to adjust the pH to 11. Then dichloroethane was added for extraction to obtain an aqueous layer. Carbon dioxide was introduced into the aqueous layer. The judgment of the end point of carbon dioxide gas introduction: The supernatant was taken out by standing, carbon dioxide was introduced, and when the supernatant no longer became turbid, the introduction of carbon dioxide was stopped. The mixture of compound VI and compound VII was obtained by filtration.

[0044] Dissolve the mixture of Compound VI and Compound VII in isopropyl alcohol, introduce hydrogen chloride gas until the pH reaches 2, crystallize, filter and dry to obtain 12.9 g of Compound I. The mother liquor is concentrated, filtered, recrystallized in isopropyl alcohol and then dried to obtain 4.3 g of Compound I. The liquid chromatography analysis procedure is the same as that in Example 1, and it is found that the purity of Compound I is 97.9 wt% and the purity of Compound II is 95.2 wt%. The total yield of Compound I and Compound II is 69.1%.

[0045] Comparative Example 1 Replace the hydrochloric acid dosage with 0.85 ml of 34 wt% concentrated hydrochloric acid, and the other raw materials and procedures are the same as those in Example 1, to obtain 9.3 g of Compound I with a purity of 97.1 wt%; obtain 2.7 g of Compound II with a purity of 93.0 wt%; the total yield of Compound I and Compound II is 47.9%.

[0046] Although the present invention has been described in detail by means of the accompanying drawings and in combination with the embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, those of ordinary skill in the art can make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions should all be within the scope covered by 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; (2) adding sodium hydroxide to the reaction solution to adjust the pH value of the reaction solution to alkaline; Then, an extractant is added to extract, and a water layer is separated. Carbon dioxide is introduced into the water layer, and a white solid is precipitated in the water layer. The mixture of compound VI and compound VII is obtained by filtration; (3) dissolving a 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; 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 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.

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 temperature is 80~100℃.

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: The reaction time is 12~24h.

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 molar ratio of compound III to acid is 1:(0.2~1).

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

7. 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 extractant is one of dichloromethane or dichloroethane.

8. 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.

9. 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 polar organic solvent is one of isopropanol and anhydrous ethanol.

10. 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 introducing hydrogen chloride gas: The end point is when hydrogen chloride gas is introduced until the pH reaches 2~3.

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