A method for preparing a chloroaporphine compound

Abstract

This invention relates to a method for preparing chloromorphon compounds. By optimizing the combination of halogenating reagents and controlling reaction conditions, the method achieves regioselective introduction of chlorine atoms at the benzene ring position in morphon compounds while ensuring the stability of the molecular skeleton. The preparation method employed in this invention features mild reaction conditions, high yield, and produces chloromorphon compounds with high purity, low impurity content, and meeting pharmaceutical requirements, making it suitable for industrial production.

Description

Technical fields:

[0001] This invention relates to the field of synthetic route design and preparation technology for active pharmaceutical ingredients and intermediates, and more specifically, to a method for preparing chloromorphine and its intermediates. Technical background:

[0002] Dextromethorphan (DXM), a representative of morphine-based centrally acting antitussives, has been used clinically for half a century since its introduction in the 1960s. Its unique multiple pharmacological mechanisms endow it with multi-target therapeutic potential: namely, it exerts neuroprotective effects by antagonizing N-methyl-D-aspartate (NMDA) receptors, inhibits monoamine transporters to regulate neurotransmitter homeostasis, and exerts neuromodulation functions by activating sigma-1 receptors. Medicinal chemical modification based on its scaffold structure has always been a hot research topic.

[0003] Existing research indicates that compounds containing halogen atoms can serve as key intermediates, with the halogen atom undergoing substitution or coupling reactions with other groups to derive compounds with substituted functional groups. Notably, brominated (WO202247345A1) and iodinated (WO2023187099A1) dextromethorphan derivatives have been efficiently synthesized using mature processes such as nucleophilic substitution, and related preparation methods have been reported. However, synthetic routes for chlorodextromethorphan derivatives have not yet been reported. This is mainly attributed to the significant influence of the unique electronegativity of the chlorine atom on the reaction selectivity, and the challenge of regioselectivity control in introducing chlorine atoms at specific sites in DXM molecules using traditional halogenating reagents.

[0004]

[0005] Summary of the Invention:

[0006] The problem the invention aims to solve

[0007] To address the shortcomings of existing technologies, this invention proposes a directed synthesis method for chlorodextromethorphan derivatives. By optimizing the combination of halogenating reagents and controlling reaction conditions, the regioselective introduction of chlorine atoms into the benzene ring of dextromethorphan is achieved while ensuring the stability of the molecular skeleton. This innovation not only enriches the library of halogenated dextromethorphan derivatives but also provides a key material basis for the development of next-generation multi-target neuroactive drugs, possessing significant research value and industrialization prospects.

[0008] Solution for solving the problem

[0009] The purpose of this invention is to provide a method for preparing chlorodextromethorphan compounds that is simple to operate, convenient for post-processing, and has a high overall yield.

[0010] According to one aspect of the present invention, a chlorodextromethorphan compound of formula (I) or a pharmaceutically acceptable salt thereof is provided;

[0011]

[0012] Wherein, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, and benzyloxycarbonyl.

[0013] Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl.

[0014] According to a second aspect of the present invention, a method for preparing a chlorodextromethorphan compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, comprising the following steps:

[0015] Step (1): The compound shown in formula (I-1) undergoes a demethylation reaction to give 3-hydroxymorphinan of formula (I-2);

[0016] Step (2): The compound shown in formula (I-2) undergoes a substitution reaction with a chlorination reagent to obtain the compound shown in formula (I).

[0017]

[0018] Preferably, the reaction in step (1) is carried out under solvent- or solvent-free conditions. After the compound shown in formula (I-1) reacts with a strong acid or a boron halide reagent, water is added, followed by extraction, concentration, and purification to obtain the compound shown in formula (I-2).

[0019] In step (2), the compound shown in formula (I-2) reacts with a chlorination reagent to obtain the compound of formula (I).

[0020] Preferably, the compounds represented by formula (I-1) or formula (I-2) are selected from their basic compounds or pharmaceutically acceptable compounds; more preferably, the salts of the compounds with the structures represented by formula (I-1) or formula (I-2) are selected from hydrochloride or hydrobromide.

[0021] Preferably, the strong acid or boron halide reagent in step (1) is selected from one or more of hydrobromic acid, concentrated hydrochloric acid, boron tribromide, and boron trichloride.

[0022] Preferably, the molar ratio of the compound of formula (I-2) or its pharmaceutically acceptable salt to a strong acid or a boron halide reagent in step (1) is 1:1 to 100.

[0023] Preferably, the chlorination reagent in step (2) is selected from one or more of NCS, chlorine, and thioyl chloride.

[0024] Preferably, in step (2), the molar ratio of the compound shown in formula (I-2) or its pharmaceutically acceptable salt to the chlorinated reagent is 1:2.0 to 5.0.

[0025] Preferably, the reaction in step (2) is carried out in a solvent selected from one or more of tetrahydrofuran, acetonitrile, dioxane, dichloromethane, 1,2-dichloroethane, methyltetrahydrofuran, benzene, chlorobenzene, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, and pteropenic acid; more preferably, the solvent is acetic acid.

[0026] Preferably, the reaction temperature in step (2) is -20℃ to 100℃, more preferably -5℃ to 50℃.

[0027] According to a third aspect of the present invention, a method for preparing the compound shown in formula (II) is provided.

[0028]

[0029] Wherein, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, and benzyloxycarbonyl; Y is selected from C1-6 alkyl and benzyl.

[0030] Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl; Y is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl.

[0031] Includes the following steps:

[0032] The compound of formula (I) or a pharmaceutically acceptable salt thereof is reacted with an alkylating agent in the presence of a base, with or without a solvent, to give the compound of formula (II), characterized in that...

[0033]

[0034] Preferably, the alkylating agent is selected from iodomethane, dimethyl sulfate, trimethyl sulfoxide iodoethane, bromoethane, bromopropane, bromoisopropane, and benzyl bromide.

[0035] Preferably, the alkali is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, cesium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride.

[0036] Preferably, the solvent is selected from one or more of tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, dimethylacetamide, toluene, and chlorobenzene.

[0037] Preferably, the molar ratio of the compound of formula (I) to the alkylating agent is 1:1.0 to 10; more preferably, it is 1:1.0 to 2.

[0038] Preferably, the reaction temperature is -20℃ to 100℃, more preferably 20℃ to 100℃.

[0039] According to a fourth aspect of the present invention, a method for preparing the compound shown in formula (III) is provided.

[0040]

[0041] Wherein, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, benzyloxycarbonyl, and Y is selected from C1-6 alkyl or benzyl;

[0042] Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl; Y is selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl.

[0043] Including the following steps:

[0044]

[0045] Under solvent-free or solvent-free conditions, the compound shown in formula (II) or its salt, under the action of a reducing agent, yields the compound shown in formula (III), wherein the reducing agent is selected from palladium on carbon, platinum on carbon, and more preferably palladium on carbon.

[0046] Preferably, the reaction is carried out in a solvent selected from one or more of tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, toluene, and acetic acid.

[0047] Preferably, the dry basis content of palladium on carbon is 5-10%, and the mass ratio of compound (II) to palladium on carbon is 1:(0.01-0.2) based on the dry basis mass of palladium on carbon.

[0048] Preferably, the reaction temperature is -20℃ to 100℃, more preferably 20℃ to 100℃;

[0049] Preferably, the reaction pressure is 0.1 to 3.0 MPa.

[0050] Due to the adoption of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0051] 1. The preparation method of this invention has mild reaction conditions, few by-products, high yield, easy process control, and simple operation, making it suitable for large-scale industrial production.

[0052] 2. The preparation method of the present invention achieves regioselective introduction of chlorine atoms at the benzene ring position of morphinan compounds, and then other morphinan compounds containing other functional groups can be obtained through substitution or coupling reactions. Detailed implementation method:

[0053] To make the technical solution and beneficial effects of the present invention more apparent and understandable, a detailed description is provided below by listing specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional experimental conditions. Unless otherwise specified, all reagents and raw materials used in this invention are commercially available.

[0054] Example 1: Preparation of Compound 2

[0055]

[0056] Dextromethorphan (DXM) hydrobromide (21 g, 1.0 eq) and 48% aqueous hydrobromic acid (210 mL) were added to a 500 mL three-necked flask, and the mixture was reacted at 110 °C for 4 hours. The reaction was confirmed by thin-layer chromatography (TLC). The pH of the reaction mixture was then adjusted to 7–8 with aqueous sodium hydroxide solution, followed by extraction three times with ethyl acetate. The organic phases were combined, dried, and concentrated under reduced pressure to give compound 1 (15 g white solid) in 98% yield. 1 H NMR (400MHz, DMSO-d6) δ8.94(s,1H),6.89(d,J=8.2Hz,1H),6.62(d,J=2.5Hz,1H ),6.50(dd,J=8.2,2.5Hz,1H),2.86(d,J=17.9Hz,1H),2.67–2.65(m,1H),2.43(d d,J=18.0,5.8Hz,1H),2.31–2.23(m,5H),1.97–1.90(m,1H),1.70–1.65(m,1H), 1.62–1.54(m,2H),1.47(d,J=12.1Hz,1H),1.37–1.15(m,5H),1.07–0.97(m,1H). 13 C NMR (101MHz, DMSO-d6): δ156.10,141.32,128.83,128.05,113.36,111.73,5 7.57,47.19,45.22,42.99,42.21,37.11,36.63,26.80,26.56,23.37,22.45.

[0057] Compound 1 (1 g, 1.0 q) was added to acetic acid (10 ml) and stirred at room temperature. Thionyl chloride (1.15 g, 2.2 eq) was added dropwise, and the reaction was stirred for 4 h. The reaction was stopped by TLC. The pH was adjusted to 8-9 with 1 M sodium hydroxide solution, and the mixture was extracted with dichloromethane and concentrated under reduced pressure to give compound 2 (1.14 g, 90% yield). 1 H NMR(400MHz, DMSO-d6)δ7.16(s,1H),3.55–3.52(m,1H),2.87(d,J=17.5Hz,1H),2.67–2.59(m,2H),2.38–2.34(m,1H),2.23 (s,3H),1.92–1.86(m,1H),1.76–1.66(m,2H),1.59–1.47(m,3H),1.40–1.30(m,2H),1.14–1.07(m,2H),0.99–0.92(m,1H).

[0058] Example 2 Preparation of Compound 3

[0059]

[0060] Compound 2 (1 g, 1.0 eq) was mixed with DMF (10 mL) under nitrogen protection and cooled to 0-5 °C. Sodium hydroxide (0.15 g, 2 eq) was slowly added, and the mixture was kept at this temperature and stirred for 1 h. Iodimethane (0.52 g, 1.2 eq) was then slowly added, and the mixture was heated to room temperature and stirred for 2 h. The reaction was stopped by TLC. The reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3 (0.57 g, 55% yield).

[0061] Example 3 Preparation of Compound 3

[0062]

[0063] (1) Preparation of compound 3-1:

[0064] Compound DXM (5.0 g, 1.0 eq) was dissolved in 50 ml of ammonia water. After reacting for 0.5 h, the mixture was extracted twice with chloroform. The organic phases were combined, dried, and filtered. Potassium carbonate (4.0 g, 2.0 eq), DIPEA (7.4 g, 4.0 eq), and ethyl chloroformate (6.15 g, 4.0 eq) were added to the filtrate. Nitrogen was used for purging. The mixture was reacted at 65 °C for 7 h. TLC showed that the reaction of the starting material was complete. The mixture was cooled to about 0 °C in an ice bath and quenched with 1 M hydrochloric acid. The mixture was then washed once with sodium bicarbonate solution. The organic phases were combined, dried, concentrated, and subjected to column chromatography to obtain compound 3-1 (4.5 g of colorless liquid, yield 96%).

[0065] (2) Preparation of compound 3-2:

[0066] Compound 3-1 (4.5 g, 1.0 eq) was dissolved in 50 mL of dichloromethane, purged with nitrogen*3, and cooled to 0 °C. 2.5 M boron tribromide / dichloromethane solution (15 mL, 3 eq) was added dropwise. The reaction was carried out at 0 °C for 0.5 h. TLC confirmed complete reaction of the starting material. The mixture was cooled to approximately 0 °C, quenched with water, and the pH was adjusted to 8 with ammonia. The mixture was extracted with dichloromethane, and the combined organic phases were dried and concentrated to obtain compound 3-2 (4 g brown solid, 92% yield).

[0067] (3) Preparation of compound 3-3

[0068] Compound 3-2 (1 g, 1.0 q) was added to acetic acid (10 ml) and stirred at room temperature. Thionyl chloride (0.94 g, 2.2 eq) was added dropwise to the system, and the reaction was stirred for 4 h. The reaction was stopped by TLC. The pH was adjusted to 8-9 by adding 1 M sodium hydroxide solution, and the mixture was extracted with dichloromethane and concentrated under reduced pressure to obtain compound 3-3 (0.99 g, yield 81%).

[0069] (4) Preparation of compound 3-4

[0070] Compound 3-3 (0.99 g, 1.0 g) was placed in DMF (10 mL) under nitrogen protection and cooled to 0-5 °C. Sodium hydroxide (0.12 g, 2 eq) was slowly added, and the mixture was stirred at this temperature for 1 h. Iodomethane (0.44 g, 1.2 eq) was then slowly added, and the mixture was heated to room temperature and stirred for 2 h. The reaction was stopped by TLC. The reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 3-4 (0.8 g, 78% yield).

[0071] (4) Preparation of compound 3

[0072] Take 0.8 g (1 eq.) of compound 3-4, add 5 ml of THF, cool to 0-5 °C and stir. Then add 0.23 g (3 eq.) of lithium aluminum hydride, and heat to 50 °C for 3 h. Treatment: Quench the reaction dropwise with water under ice-water bath, adjust pH to 8-9 with 1 M NaOH solution, filter, wash the filter cake with THF, collect the filtrate, concentrate the filtrate under reduced pressure, purify by column chromatography, and salt with ethyl hydrochloride to give compound 3 hydrochloride (0.6 g off-white solid, 73% yield). 1H NMR(400MHz,DMSO-d6)δ10.25(s,1H),7.43(s,0.2H),7.39(s,0.8H),3.78(s, 3H),3.60(s,1H),3.19–3.13(m,3H),2.98(d,J=5.1Hz,0.5H),2.77(d,J=4.9H z,2.5H),2.67(s,0.5H),2.33(s,0.5H),2.05–1.96(m,2H),1.81–1.77(m,1H) ,1.64–1.55(m,3H),1.49–1.35(m,1H),1.19–1.12(m,1H),1.04–0.95(m,1H).

[0073] Example 4: Preparation of Compound 4

[0074]

[0075] Compound 2 (1 g, 1.0 eq) was added to methanol (10 mL), Pd / C (0.1 g, 10%), and the mixture was purged with hydrogen using a hydrogen balloon. The mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 4 (0.8 g, off-white solid, 89% yield).

[0076] Example 5: Preparation of Compound 5

[0077]

[0078] Compound 3 (0.5 g, 1.0 eq) was added to 5 mL of methanol and 10% Pd / C (0.05 mg, 10%). The mixture was then replaced with hydrogen gas, and stirred overnight at room temperature using a hydrogen balloon. The mixture was filtered and concentrated under reduced pressure to obtain compound 4 (0.3 g, 67% yield). 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.19(d,J=8.5Hz,1H),7.08(d,J=8.6Hz,1H),3.83(s,3H),3 .66(d,J=14.0Hz,1H),3.58–3.49(m,1H),3.14(d,J=3.6Hz,1H),3.09(d,J=13.2Hz,1H),2.94(d,J= 5.1Hz,1H),2.72(d,J=4.9Hz,3H),2.46–2.36(m,1H),2.18(dt,J=12.7,3.3Hz,1H),1.98–1.83(m,2 H),1.62–1.44(m,3H),1.38–1.34(m,1H),1.28–1.24(m,1H),1.15–1.09(m,1H),1.02–0.93(m,1H).

[0079] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations included in the claims. Various modifications and changes can be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments can be arbitrarily combined to form other embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments only illustrate several implementations of the present invention and do not limit the scope of protection of this patent.

Claims

1. A chloromorphinan compound of formula (III) or a pharmaceutically acceptable salt thereof; in, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, benzyloxycarbonyl, and Y is selected from H, C1-6 alkyl, and benzyl. Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl, and Y is selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl.

2. A method for preparing a chloromorphinan compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: Step (1): The compound shown in formula (I-1) undergoes a demethylation reaction to give 3-hydroxymorphinan of formula (I-2); Step (2): The compound shown in formula (I-2) reacts with the chlorination reagent to obtain the compound shown in formula (I); in, The compound represented by formula (I-1) or formula (I-2) is selected from its basic form or pharmaceutically acceptable salt, preferably a basic compound or its hydrochloride or hydrobromide salt; The reaction in step (1) is carried out under solvent- or solvent-free conditions. After the compound shown in formula (I-1) reacts with a strong acid or a boron halide reagent, water is added, followed by extraction, concentration, and purification to obtain the compound shown in formula (I-2).

3. The preparation method according to claim 2, characterized in that: The reaction in step (2) is carried out in a solvent selected from one or more of tetrahydrofuran, acetonitrile, dioxane, dichloromethane, 1,2-dichloroethane, methyltetrahydrofuran, benzene, chlorobenzene, formic acid, acetic acid, propionic acid, butyric acid, valeric acid, and pteropenic acid. Preferably, the solvent is acetic acid. And / or, the strong acid or boron halide reagent in step (1) is selected from one or more of hydrobromic acid, concentrated hydrochloric acid, boron tribromide, and boron trichloride; And / or, the molar ratio of the compound of formula (I-2) in step (1) to a pharmaceutically acceptable salt thereof and a strong acid or a boron halide reagent is 1:1 to 100. And / or, the chlorination agent in step (2) is selected from one or more of NCS, chlorine, and thioyl chloride; And / or, in step (2), the molar ratio of the compound of formula (I-2) or its pharmaceutically acceptable salt to the chlorinated reagent is 1:2.0 to 5.0; And / or, the reaction temperature in step (2) is -20℃ to 100℃, more preferably -5℃ to 50℃.

4. A method for preparing a chloromorphinan compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps: in, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, and benzyloxycarbonyl; Y is selected from C1-6 alkyl and benzyl. Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl; Y is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl. Includes the following steps: The compound shown in formula (I) or its pharmaceutically acceptable salt is reacted with an alkylating agent in the presence of a base, with or without a solvent, to give the compound shown in formula (II). The alkylating agent is selected from iodomethane, dimethyl sulfate, trimethyl sulfoxide iodoethane, bromoethane, bromopropane, bromoisopropane, and benzyl bromide; The alkali is selected from one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium acetate, potassium acetate, cesium carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride. The solvent is selected from one or more of tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, dimethylacetamide, toluene, and chlorobenzene; The molar ratio of the compound of formula (I) to the alkylating agent is 1:1.0 to 10, preferably 1:1.0 to 2; The reaction temperature is -20℃ to 100℃, preferably 20℃ to 100℃.

5. A method for preparing a chloromorphinan compound of claim 1 (III) or a pharmaceutically acceptable salt thereof, comprising the following steps: Under solvent-free or solvent-free conditions, the compound shown in formula (II) or its salt, under the action of a reducing agent, yields the compound shown in formula (III), wherein the reducing agent is selected from palladium on carbon, platinum on carbon, and more preferably palladium on carbon. in, X is selected from H, C1-6 alkyl, C1-6 alkoxycarbonyl, and benzyloxycarbonyl; Y is selected from C1-6 alkyl and benzyl. Preferably, X is selected from H, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, ethoxycarbonyl, methoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, and benzyloxycarbonyl; Y is selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, and benzyl. In particular The reaction is carried out in a solvent selected from one or more of tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, toluene, and acetic acid; and / or The palladium on carbon has a dry basis content of 5-10%, and the mass ratio of compound (II) to palladium on carbon is 1:(0.01-0.2) based on the dry matrix mass of palladium on carbon; and / or The reaction temperature is -20℃ to 100℃, more preferably 20℃ to 100℃; and / or The reaction pressure is 0.1–3.0 MPa.

Images