Electrochemical preparation of dasotraline

Abstract

The present application relates to the electro-reduction preparation method of 1,2,3,4-tetrahydro-1-naphthylamine compound (I) and its hydrochloride, which is characterized in that 3,4-dihydronaphthalene-1(2H)-ketoxime compound (II) is prepared into 1,2,3,4-tetrahydro-1-naphthylamine compound (I) by electro-reduction method in alkaline solution; its preparation reaction is as follows: in a divided electrolytic cell, the alkaline solution of 3,4-dihydronaphthalene-1(2H)-ketoxime compound (II) and an organic solvent are used to form the cathode electrolyte; the anode electrolyte is an alkaline solution; the cathode electrolytic product of 1,2,3,4-tetrahydro-1-naphthylamine compound (I) is obtained by electro-reduction reaction.

Description

Technical Field

[0001] This invention relates to a novel method for the electroreduction preparation of dasoctraline, specifically a method for the electroreduction preparation of 4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-ketooxime compounds and their hydrochlorides. Background Technology

[0002] In 2007, Alain et al. [Iap bir domain binding compounds, WO 2007104162A1, 2007.09.20] reported that compound 2 containing the 1,2,3,4-tetrahydro-1-naphthylamine structure promoted apoptosis in SMA cells, and its biological activity and clinical applications are currently under investigation. Also in 2007, James et al. [Bir domain binding compounds, WO2007101347, 2007.9.13] selected (R)-1,2,3,4-tetrahydronaphthyl-1-amine to prepare compound 2, with an overall yield of 57%. The specific synthetic route is as follows:

[0003]

[0004] Elise et al. [Benzhydryl amide derivatives as cannabinoid receptor antagonists of inverse agonists, WO 2007064272A1, 2007.06.07] reported that N-(1,2,3,4-tetrahydronaphthyl)thiourea (3) has a good therapeutic effect on obesity; in 2004, Bhandari et al. [Synthesis of tetrahydronaphthyl thioureas as potent appetite suppressants. Bioorganic & Medicinal Chemistry, 2004, 12(15): 4189-4196.] 1,2,3,4-tetrahydro-1-naphthylamine was reacted with benzoyl isothiocyanate to give N-benzoyl-N'-(1,2,3,4-tetrahydronaphthyl-1-yl)thiourea in 60% yield; deprotection was carried out in ethanol with 10% KOH to give N-(1,2,3,4-tetrahydronaphthyl-1-yl)thiourea 3.

[0005]

[0006] Tangallapally et al. [Synthesis and Evaluation of Nitrofuranylamides as Novel Antituberculosis, Agents. J. Med. Chem., 2004, 47: 5276-5283.] reported that compound 4 has good anti-tuberculosis activity. In 2004, Tangallapally et al. [Synthesis of tetrahydronaphthylthioureas as potent appetite suppressants, J. Med. Chem., 2004, 47(21): 5276-5283.] described a method using 98% EDCI and N,N-dimethylaminopyridine (DMAP) activated in DMF, 5-nitro-2-furanic acid and 1-amino-1,2,3,4-tetrahydronaphthalene, reacted at 25 °C for 14 h to obtain compound 4.

[0007]

[0008] In 2007, Elise et al. [Benzhydryl amide derivatives as cannabinoid receptor antagonists or inverse agonists, WO2007064272A1, 2007.06.07] reported on the clinical study of 1,2,3,4-tetrahydro-1-naphthylamine derivatives as cannabinoid receptor antagonists for anti-obesity.

[0009]

[0010] In 2012, Zhang Ming et al. [Resolution and racemic method of 1-amino-1,2,3,4-tetrahydronaphthalene, CN102675123A, 2012.9.19] selected 3,4-dihydro-1-(2H)-naphthone oxime to racemic 1,2,3,4-tetrahydro-1-naphthylamine by Pd / C reduction, with a yield of 96%.

[0011]

[0012] In 1998, Gutman et al. [Stereo-and regioselectivity in asymmetric synthesis of α-amino substituted benzocyclic compounds. Tetrahedron: Asymmetry, 1998, 9(24): 4369-4379] chose to react 3,4-dihydronaphthyl-1(2H)-one with (S)-1-phenylethane-1-amine to obtain intermediate 6, which was then isomerized at -30℃ to intermediate 7, and then reduced with Pd / C to obtain (R)-1,2,3,4-tetrahydro-1-naphthylamine.

[0013]

[0014] In 2005, Jin Wanzhu et al. [Method for preparing chiral amines, CN1633427A, 2005.6.29] selected 3,4-dihydronaphthyl-1(2H)-ketooxime and hydrogenated it with Pd / C lipase to obtain (R)-N-acetyl-1-phenyl-ethylamine. After reflux in 1.2N HCl for 9 h, (R)-1,2,3,4-tetrahydro-1-naphthylamine was obtained with a yield of 70% and 97% ee.

[0015]

[0016] In 2001, Takei et al. [Ruthenium-catalyzed asymmetric hydrosilylation of ketoximes using chiral oxazolinylferrocenylphosphines, Chem. Commun., 2001, (22): 2360-2361] selected 12,3,4-tetrahydronaphthone oximes via asymmetric hydrosilylation with a chiral ruthenium complex (8), followed by acid hydrolysis to obtain the corresponding selective (R)-1,2,3,4-tetrahydro-1-naphthylamine; chiral ruthenium complex (8): RuCl2(PPh3) (oxazolinylferrocenylphosphine); yield 71%, 79% ee.

[0017]

[0018] In 2021, Lei et al. [Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D2O as a Deuterium Source, J.Org.Chem., 2021, 86(3): 2907-2916.] selected 12,3,4-tetrahydronaphthone oxime. Under argon protection, they selected a heavy water:raw material mass ratio of 1:4.97, added 10 mL of 0.1 mol / L samarium diiodide tetrahydrofuran solution, and stirred vigorously at room temperature for 15 minutes. The crude product was then added to cyclopentyl methyl ether hydrochloride solution to obtain 1-deuterated-2,3,4-trihydro-1-naphthylamine hydrochloride with a yield of 98% and a deuteration rate of 95%.

[0019]

[0020] In 2012, Pakulski et al. [Enantioselective reduction of ketoxime ethers with borane–oxazaborolidines and synthesis of the key intermediate leading to (S)-rivastigmine, Tetrahedron: Asymmetry. 2012, 23(9): 716-721.] selected 12,3,4-tetrahydronaphthone oxime, first benzyl etherified with a benzyl ether:catalyst:borane / THF molar ratio of 1:1.25:7.5, reacted for 48 h, and then acidified in hydrochloric acid for 24 h to obtain 1,2,3,4-tetrahydro-1-naphthylamine in 70% yield.

[0021]

[0022] In 2013, Cheng Peng et al. [Synthesis of monoamine oxidase inhibitor 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride. Journal of Chongqing Medical University. 2013.38(6):580-582.] prepared 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride by acylation, reduction, cyclization, condensation, reduction and salt formation of benzene, with an overall yield of 43.6%; the yield of the reduction reaction was 82%.

[0023]

[0024] In 2005, Rivera et al. [Facile Rearrangement of O-Silylated Oximes on Reduction with Boron Trifluoride / Borane, J.Org.Chem., 2005, 70(24): 10132-10134.] selected 1,2,3,4-tetrahydronaphthylsilyl oxime and reduced it with BH3 at 55 °C for 1 h to obtain 1,2,3,4-tetrahydro-1-naphthylamine with a yield of 33%.

[0025]

[0026] In 1985, Welch et al. [Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalen-amine, US4536518A, 1985.8.20] selected (S)-phenyl(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)methanol (9) and debenzylated it with hydrochloric acid to obtain (S)-1,2,3,4-tetrahydro-1-naphthaleneamine.

[0027]

[0028] In 2008, Zeng Peng et al. [Preparation of (R)-α-tetrahydronaphthalene, Frontiers of Research and Development, 2008, 16(15):28-29.] selected 3,4-dihydronaphthyl-1(2H)-one and reacted it with hydroxylamine hydrochloride to obtain 3,4-dihydronaphthyl-1(2H)-one oxime, which was then reduced by reflux with metallic sodium for 1 h to obtain 1,2,3,4-tetrahydro-1-naphthylamine with a yield of 98%.

[0029]

[0030] On May 14, 2020, the U.S. Food and Drug Administration (FDA) accepted the New Drug Application (NDA) for dasotraline (10, demethylsertraline) for the treatment of moderate to severe bulimia nervosa (BED); chemical name: (1R,4S)4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine (10).

[0031]

[0032] The 2008 Chinese invention patent [Application of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine in the treatment of cancer, CN101222917A, 2008.7.16.] describes the anti-proliferative activity of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine and its isomers against more than 30 kinds of tumor cells, including lung cancer and breast cancer. The 2009 Chinese invention patent [Treatment of CNS Disorders with trans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine and its formamide, CN101712626B, 2013.11.20] describes (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine and (1S,4R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine as being used to treat central nervous system (CNS) disorders mediated by monoamine activity.

[0033] In 2000, Du Kangping et al. [Synthesis of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine by Luccard reaction, Chinese Journal of New Drugs, 2000, 9(6):394-395.] described the preparation of 4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-one by Luccard reaction: 4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-one was reacted at 180℃ for 4 h in the presence of formamide and formic acid, with a yield of 60%.

[0034]

[0035] In 2021, Ouyang Qin et al. [A Sertraline Side-Chain Amino Structure Derivative and Its Preparation Method and Application, CN112661657, 2021.04.16] selected 4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-one as the starting material, reacted it with ammonium acetate in isopropanol at 80℃ for 2 h, and then reduced it with sodium borohydride for 16 h to obtain 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine.

[0036]

[0037] In 2008, Fabrice et al. [Processes for preparing desmethylsertraline or apharmaceutically acceptable salt thereof, WO2008065177A1, 2008.6.5] selected 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthone and iminated it with p-methoxybenzylamine to give the (1S,4S)- and (1R,4R)-cis isomers of benzylamine. The benzylamine was then resolved and debenzylated using (+)-tartaric acid to give the (+)-tartrate desmethylsertraline, with an overall yield of less than 3%.

[0038]

[0039] In 2014, Zhao et al. [Preparation of chiral amides and amines, CN103588659A, 2014.02.19] selected 4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-ketooxime (11) for in-situ acylation to obtain intermediate (12), which was then reduced and acylated to obtain acylated enamide (13) and diacylate (14). The mixture was treated with sodium hydroxide, and hydrogen sulfate / tetrabutylammonium hydroxide was used as a phase transfer agent to convert intermediate (14) into enamide (13). Enamide (13) was hydrogenated in isopropanol under (R,R)-MeBPE(COD)RhBF4 catalysis with hydrogen gas (90 psig) for 7.5 h to obtain intermediate (15); transacetamide (15) was refluxed in propanol-hydrochloric acid for 48 h to deacetylate to obtain ammonium hydrochloride salt (16) with a yield of 80%.

[0040]

[0041] In 2018, Waltham et al. [Enamide process, US20180215702A1, 2018.8.2] selected (S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthyl-1(2H)-one and hydroxylamine hydrochloride, and under nitrogen protection, generated the intermediate ketoxime (11). This intermediate was then acylated in situ to give the O-acetyloxime intermediate (12), which was further isomerized to give enamide (13) in 89% yield. Enamide (13) was then hydrogenated in isopropanol with the addition of (R,R)-MeBPE(COD)RhBF4 and hydrogen gas (90 psig) to give the (1R,4S)-acetamide intermediate (15) in 83% yield. (1R,4S)-acetamide (15) was then deacetylated with oxaloyl chloride in anhydrous THF to generate compound 10 in 86% yield.

[0042]

[0043] In 2021, Roberto et al. [Preparation of enamide intermediate for the synthesis of dasotraline, EP3800178A1, 2021.4.7] described the reaction of (S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthone with NH3 methanol solution at 0°C, followed by the addition of 2 equivalents of Ti(OiPr)4, heating to 20°C, and reacting for 48 h. After cooling, triethylamine and acetic anhydride were added, and the reaction was continued for another 24 h to obtain N-((S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphth-1-yl)acetamide. 13), yield 85.6%; then hydrogenated with (R,R)-Norphos(COD)Rh-BF4 to give N-((1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphth-1-yl)acetamide (15), yield 91.5%; reacted with concentrated hydrochloric acid in isopropanol to give (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride (16), yield 83.3%.

[0044] Summary of the Invention

[0045] The technical problem solved by this invention is to provide an electroreduction method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds (Ⅰ) and their hydrochlorides, so as to overcome the problems of classical reduction reactions.

[0046] To solve the technical problem of this invention, the present invention provides the following technical solution:

[0047] This invention provides an electroreduction method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds (Ⅰ) and their hydrochlorides, characterized in that 1,2,3,4-tetrahydro-1-naphthylamine compounds (Ⅰ) are prepared by electroreduction of 3,4-dihydronaphth-1(2H)-ketooxime compounds (A) in an alkaline solution; the preparation reaction is as follows:

[0048]

[0049] In a separate electrolytic cell, an alkaline solution of 3,4-dihydronaphthyl-1(2H)-ketooxime compound (A) and an organic solvent are used to form the cathode electrolyte; the anolyte is an alkaline solution; the cathode electrolyte is obtained by electroreduction reaction to yield 1,2,3,4-tetrahydro-1-naphthylamine compound (I); the cathode electrolyte is post-treated to obtain 1,2,3,4-tetrahydro-1-naphthylamine compound, which is then precipitated with HCl gas to form a salt, yielding 1,2,3,4-tetrahydro-1-naphthylamine compound hydrochloride.

[0050] The cathode working electrode voltage is 1.0V to 3.0V relative to the reference electrode; the cathode working electrode current density is 0.4A / cm². 2 ~1.2A / cm 2 Between 0.4 and 1.2 A; and between 25°C and 85°C for electrolysis.

[0051] The concentration of 3,4-dihydronaphthyl-1(2H)-ketooxime compound (A) was between 5.0 g / L and 20.0 g / L;

[0052] The alkaline solution is selected from: potassium hydroxide solution or sodium hydroxide solution;

[0053] Alkali concentration selection: 0.1 mol / L to 5 mol / L; preferred concentrations: 0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 1 mol / L, 2 mol / L, 3 mol / L, or 5 mol / L.

[0054] The reference electrode for the partitioned electrolytic cell is either a saturated potassium chloride calomel electrode or an Ag / AgCl electrode.

[0055] The cathode of the partitioned electrolytic cell is: a brass electrode, a copper electrode, a zinc sheet, a nickel electrode, a lead electrode, or a platinum electrode.

[0056] The anode of the partitioned electrolytic cell is a platinum mesh electrode, a platinum sheet electrode, or a graphite electrode.

[0057] The diaphragm of the partitioned electrolytic cell is either an HF-101 strong acid cation exchange membrane or an N-117 proton exchange membrane.

[0058] The organic solvent in the cathode electrolyte is selected from any one or more of acetonitrile, butyronitrile, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide.

[0059] The volume ratio of organic solvent to alkaline solution in the cathode electrolyte is selected from 1:1 to 1:10.

[0060] Recrystallization can separate the four cis and trans isomers (Ⅰb) into two cis isomers and two trans isomers. The two trans enantiomers are resolved by chiral organic acids such as chiral tartaric acid or chiral mandelic acid to obtain (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine (dassoserine, 10). The two cis enantiomers are resolved by chiral organic acids such as chiral tartaric acid or chiral mandelic acid to obtain (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine (17). Compound 17 is methylated to obtain (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine (sertraline, 18).

[0061]

[0062] Beneficial technical effects:

[0063] This invention relates to a method for the electroreduction preparation of dasoctraline. The method for the electroreduction preparation of 1,2,3,4-tetrahydro-1-naphthylamine compounds (Ⅰ) and their hydrochlorides has the following advantages:

[0064] (1) No toxic or dangerous reducing agents are needed in the reduction reaction. "Electrons" are clean reaction reagents and are an important part of the development of "green pharmaceutical industry".

[0065] (2) No additional catalyst is needed during the electroreduction process; high-purity and high-yield intermediates can be obtained simply in an alkaline solution.

[0066] (3) In industrial production, it simplifies the process, reduces production costs, and is safe and environmentally friendly, making it suitable for large-scale promotion and application.

[0067] Electroreduction reactions do not require toxic or hazardous reducing agents, making them an important component of the development of a "green pharmaceutical industry." High-purity and high-yield intermediates can be obtained simply in an alkaline solution without the need for additional catalysts.

[0068] The electroreduction preparation method of 1,2,3,4-tetrahydro-1-naphthylamine compound (Ⅰ) and its hydrochloride salt of the present invention simplifies the process and reduces the production cost in the industrial production of dasoctreolin, and is virtually pollution-free to the environment, making it suitable for large-scale application.

[0069] Attached Figure Description

[0070] Appendix Figure 1 Schematic diagram of a partitioned electrolytic cell Detailed Implementation

[0071] The following examples are intended to illustrate the invention and not to further limit it.

[0072] Example 1

[0073] Electroreduction preparation of 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride

[0074]

[0075] A partitioned electrolytic cell was installed, using an N-117 proton exchange membrane and a saturated potassium chloride calomel electrode as the reference electrode. In the cathode chamber, 0.32 g (1.99 mmol) of 3,4-dihydronaphthyl-1(2H)-ketooxime was added, dissolved in 5 mL of methanol, and 40 mL of 0.2 mol / L KOH solution was added as the electrolyte. In the anode chamber, 45 mL of 5 mol / L KOH solution was added as the electrolyte. The cathode electrode was a 2×2 cm zinc sheet. 2 The anode electrode is a platinum sheet (1×1cm). 2 The cell voltage was 8.5V, the current was 0.6A, the working potential was around 2.2V, and the temperature was constant at 50℃ for 4 hours. The cathode liquid was removed by rotary evaporation to remove the methanol solvent. The remaining alkaline aqueous solution was extracted twice with ethyl acetate, and the pH was adjusted to 8-9 with dilute hydrochloric acid solution. The extraction was repeated twice. The extracts were combined, dried over anhydrous Na₂SO₄, and the solvent was removed to obtain a pale yellow-white oily compound. This compound was dissolved by adding 3 mL of diethyl ether, and HCl gas was introduced, resulting in a white solid (1,2,3,4-tetrahydro-1-naphthylamine hydrochloride). The solvent was rotary evaporated to obtain a white solid, which was washed with ethyl acetate, and the filter cake was dried to obtain a white solid powder—0.341 g of 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, with a yield of 93.2%. 1 H NMR (400MHz, DMSO-d6) δ: 8.62 (s, 3H, NH3 + ), 7.65~7.15 (m, 4H, benzene ring), 4.40 (s, 1H, CH), 2.85~2.65 (m, 2H, 4-CH2), 2.15~1.65 (m, 4H, 2,3-CH2CH2).

[0076] Example 2

[0077] Preparation of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride

[0078]

[0079] A partitioned electrolytic cell was installed, using an N-117 proton exchange membrane and a saturated potassium chloride calomel electrode as the reference electrode. In the cathode chamber, 0.31 g (1.00 mmol) of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthyl-1-one oxime was added, dissolved in 15 mL of ethanol, and then 30 mL of 0.2 mol / L KOH solution was added as the electrolyte. In the anode chamber, 45 mL of 5 mol / L KOH solution was added as the electrolyte. The cathode electrode was a 2×2 cm zinc sheet. 2 The anode electrode is a platinum sheet (1×1cm). 2The cell voltage was 14V, the current was 0.6A, the working potential was around 2.1V, the temperature was constant at 50℃, and the electrolysis was carried out for 7 hours. The cathode liquid was extracted twice with ethyl acetate, the pH was adjusted to 8-9 with dilute hydrochloric acid solution, and then extracted twice more. The extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed to obtain a light yellow oily compound. The compound was dissolved by diluting it with 5 mL of diethyl ether, and HCl gas was introduced, resulting in a white solid [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride]. The solvent was rotary evaporated to obtain a white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain a white solid powder—0.310 g of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, with a yield of 94.2%. 1 H NMR (400MHz, DMSO-d6) δ: 8.75 (s, 3H, NH3 + ), 7.80~6.70 (m, 7H, benzene ring), 4.65~4.45 (m, 1H, 4-CH), 4.35~4.05 (m, 1H, 1-CH), 2.35~1.75 (m, 4H, CH2CH2).

[0080] Example 3

[0081] Preparation of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride

[0082]

[0083] A partitioned electrolytic cell was installed, using an N-117 proton exchange membrane and a saturated potassium chloride calomel electrode as the reference electrode. In the cathode chamber, 0.31 g (1.00 mmol) of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthyl-1-one oxime was added, dissolved in 15 mL of ethanol, and then 30 mL of 0.2 mol / L KOH solution was added as the electrolyte. In the anode chamber, 45 mL of 5 mol / L KOH solution was added as the electrolyte. The cathode electrode was a 2×2 cm zinc sheet. 2 The anode electrode is a platinum sheet (1×1cm). 2 The cell voltage was 14V, the current was 0.8A, the working potential was around 2.1V, the temperature was constant at 50℃, and the electrolysis lasted for 7 hours. The cathode liquid was extracted twice with ethyl acetate, the pH was adjusted to 8-9 with dilute hydrochloric acid solution, and then extracted twice more. The extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed to obtain a light yellow oily compound. 5 mL of diethyl ether was added to dissolve the compound, and HCl gas was introduced, resulting in a white solid [4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride]. The solvent was rotary evaporated to obtain a white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain a white solid powder—0.320 g of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, with a yield of 97.3%.1 H NMR (400MHz, DMSO-d6) δ: 8.75 (s, 3H, NH3 + ), 7.80~6.70 (m, 7H, benzene ring), 4.65~4.45 (m, 1H, 4-CH), 4.35~4.05 (m, 1H, 1-CH), 2.35~1.75 (m, 4H, CH2CH2).

[0084] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, the specification and drawings should be considered illustrative rather than restrictive.

Claims

1. A method for the electroreduction preparation of a 1,2,3,4-tetrahydro-1-naphthylamine compound represented by Formula I, characterized in that... In alkaline solution, the 3,4-dihydronaphthyl-1(2H)-ketoxime compound shown in formula A is electroreduced to prepare 1,2,3,4-tetrahydro-1-naphthylamine compounds; the preparation reaction is as follows: In a partitioned electrolytic cell, the cathode electrolyte is composed of an alkaline solution of a 3,4-dihydronaphthyl-1(2H)-ketooxime compound as shown in Formula A and an organic solvent; the anode electrolyte is an alkaline solution. The cathode electrolysis products of 1,2,3,4-tetrahydro-1-naphthylamine compounds were obtained by electroreduction reaction; The cathode electrolysis products were post-treated to obtain 1,2,3,4-tetrahydro-1-naphthylamine compounds, which were then precipitated with HCl gas to form salts, yielding 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride. The cathode working electrode voltage is 1.0 V to 3.0 V relative to the reference electrode; the cathode working electrode current density is selected from 0.15 A / cm². 2 The current is selected from 0.6A, and the electrolysis temperature is selected from 25℃ to 85℃. The alkaline solution is selected from sodium hydroxide solution or potassium hydroxide solution; the reference electrode of the diaphragm electrolytic cell is selected from saturated potassium chloride calomel electrode or Ag / AgCl electrode.

2. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The cathode of the partitioned electrolytic cell is selected from brass electrodes, copper electrodes, zinc sheets, nickel, lead, or platinum electrodes.

3. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The anode of the partitioned electrolytic cell is selected from: platinum mesh, platinum sheet or graphite electrode; the diaphragm of the partitioned electrolytic cell is selected from: N-117 proton exchange membrane or HF-101 strong acid cation exchange membrane.

4. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The organic solvent in the cathode electrolyte is selected from any one or more of acetonitrile, butyronitrile, methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide.

5. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The concentration of 3,4-dihydronaphthyl-1(2H)-ketooxime compounds in the cathode electrolyte is between 5.0 g / L and 20.0 g / L.

6. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The concentration of the alkali solution is selected from: 0.1 mol / L, 0.2 mol / L, 0.5 mol / L, 1mol / L, 2 mol / L, 3 mol / L or 5mol / L.

7. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The volume ratio of organic solvent to alkaline solution in the cathode electrolyte is selected from 1:1 to 1:

10.

8. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that, The cathode electrode of the partitioned electrolytic cell is selected from zinc sheet electrodes; the anode electrode of the partitioned electrolytic cell is selected from platinum mesh electrodes.

9. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that... The electroreduction preparation process of 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride is as follows: A partitioned electrolytic cell was installed, using an N-117 proton exchange membrane and a saturated potassium chloride calomel electrode as the reference electrode. 0.32 g of 3,4-dihydronaphthyl-1(2H)-ketooxime was added to the cathode chamber, dissolved in 5 mL of methanol, and 40 mL of 0.2 mol / L KOH solution was added as the electrolyte. 45 mL of 5 mol / L KOH solution was added to the anode chamber as the electrolyte. The cathode electrode area was 2 × 2 cm². 2 Zinc sheet, anode electrode area is 1×1cm 2 A platinum sheet was used. The cell voltage was 8.5 V, the current was 0.6 A, the working potential was around 2.2 V, and the temperature was constant at 50℃ for 4 h. The cathode liquid was rotary evaporated to remove the methanol solvent. The remaining alkaline aqueous solution was extracted twice with ethyl acetate. The pH was adjusted to 8-9 with dilute hydrochloric acid solution, and the extraction was repeated twice. The extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed to obtain a pale yellow-white oily compound. The compound was dissolved by adding 3 mL of diethyl ether and then HCl gas was introduced. A white solid appeared—1,2,3,4-tetrahydro-1-naphthylamine hydrochloride. The solvent was rotary evaporated to obtain a white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 0.341 g of white solid powder 1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, with a yield of 93.2%.

10. The method for preparing 1,2,3,4-tetrahydro-1-naphthylamine compounds by electroreduction as described in claim 1, characterized in that... The preparation process of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride is as follows: A partitioned electrolytic cell was installed, using an N-117 proton exchange membrane and a saturated potassium chloride calomel electrode as the reference electrode. In the cathode chamber, 0.31 g of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthyl-1-one oxime was added, dissolved in 15 mL of ethanol, and then 30 mL of 0.2 mol / L KOH solution was added as the electrolyte. In the anode chamber, 45 mL of 5 mol / L KOH solution was added as the electrolyte. The cathode electrode area was 2 × 2 cm². 2 Zinc sheet, anode electrode area is 1×1cm 2 A platinum sheet was used. The cell voltage was 14 V, the current was 0.6 A, the working potential was around 2.1 V, and the temperature was kept constant at 50℃ for 7 h. The cathode liquid was extracted twice with ethyl acetate, and the pH was adjusted to 8-9 with dilute hydrochloric acid solution. The extraction was repeated twice. The extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed to obtain a light yellow oily compound. The compound was dissolved by diluting it with 5 mL of diethyl ether and then HCl gas was introduced. A white solid, 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, appeared. The solvent was rotary evaporated to obtain a white solid. The solid was washed with ethyl acetate, and the filter cake was dried to obtain 0.310 g of white solid powder 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride, with a yield of 94.2%.

Images