Preparation method and intermediate of alasset hydrochloride

Abstract

The invention provides a preparation method and intermediates of alasset hydrochloride, which comprises the following steps: reacting an initial raw material as shown in a formula 1, which is protected by bare phenolic hydroxyl groups or different protecting groups, with bis (pinacolato) diboron to obtain an intermediate as shown in a formula 2, carrying out coupling reaction on the intermediate and a compound as shown in a formula 3 to obtain a corresponding hydroxyl-protected intermediate as shown in a formula 4, and separating and purifying the intermediate to obtain the alasset hydrochloride. The preparation method comprises the following steps: carrying out catalyst pressurized hydrogenation, carrying out asymmetric chiral hydrogenation to obtain an intermediate as shown in a formula 5, carrying out substitution or reductive amination to obtain an intermediate as shown in a formula 6, carrying out nucleophilic substitution on the intermediate as shown in a formula 7 to obtain an intermediate as shown in a formula 8, and carrying out deprotection to obtain a target product as shown in a formula I. According to the invention, a chiral resolution link in the existing preparation technology is avoided, and a chiral group is introduced through asymmetric hydrogenation, so that the yield is greatly improved, the production cost is greatly reduced, the tedious and tedious synthesis steps in the original process are shortened, and the post-treatment is simpler and more controllable.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, relates to the preparation of elastomeric, and in particular to a preparation method and an intermediate of elastomeric hydrochloride. Background Art

[0002] Elacestrant is an anti-breast cancer drug developed by Menarini of Italy and Square Health of the United States. It was approved for marketing by the FDA on January 27, 2023. It is the first selective estrogen receptor degrader that can be used for patients with advanced or metastatic breast cancer.

[0003] Elastran (RAD1901) is a selective estrogen receptor downregulator / degrader, or SERD, that crosses the blood-brain barrier and is particularly suitable for the treatment of metastatic breast cancer. RAD1901 has been shown to have good selectivity for the estrogen receptor (ER) and has both estrogen-like and anti-estrogenic effects in different tissues. In many cancers, hormones, such as estrogen, stimulate tumor growth, so the desired therapeutic goal is to block this estrogen-dependent growth while inducing apoptosis of cancer cells. SERDs have the potential to become an emerging class of endocrine therapeutics that can directly induce ER degradation, potentially removing estrogen growth signals in ER-dependent tumors without developing ligand-independent resistance.

[0004] Elacestrant (Chinese name: Elacestrant or Elacestrant), usually exists in the form of dihydrochloride, with a molecular weight of 531.56 and a molecular formula of C30H40N2O2Cl2. Its structural formula is as follows:

[0005]

[0006] At present, there are few reports on the preparation method of elastostat. Fangyuan Health Company disclosed the following reaction route in the prior art WO2020167855A1:

[0007] The method is an original research route (as shown below), wherein compound 1 (7-benzyloxy-3-bromo-1,2-dihydronaphthalene) and diboronic acid pinacol ester are reacted under the action of a palladium catalyst to obtain an active intermediate 2, which is coupled with compound 3 (N-acetyl-2-bromo-5-methoxyaniline) to obtain an intermediate (N-[2-[3,4-dihydro-6-benzyloxy]-2-naphthyl]-5-methoxyphenyl]acetamide) as shown in formula 4, and then reduced by Pd(OH)2 / C pressure hydrogenation to obtain an intermediate (N-[5-methoxy- 2-(1,2,3,4-tetrahydro-6-hydroxy-2-naphthyl)phenyl]acetamide), which is then hydrolyzed to obtain an intermediate as shown in Formula 6 (6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydro-2-naphthol), which is chirally resolved by D-(+)-DBTA to obtain the target configuration intermediate 7, which is firstly reacted with the intermediate as shown in Formula 8 to form an imine intermediate, which is then reduced by NaBH(OAc)3 and further ethylated on the amino group to obtain the intermediate as shown in Formula 9, and the target elastomeric hydrochloride is obtained by reducing the amide carbonyl with sodium borohydride.

[0008] Original research route:

[0009]

[0010] However, the above method for synthesizing elastomeric hydrochloride has lengthy reaction steps, complicated post-treatment, and low resolution yield. In addition, the noble metal palladium catalyst is used multiple times during the synthesis process, resulting in a high cost for synthesizing the final product.

[0011] Chengdu Inodabo Pharmaceutical Technology Co., Ltd. announced a method for synthesizing elastomeric, including CN117229157A (as shown in A) and CN117229156A (as shown in B). The method is to obtain intermediate 1 ((R)-6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol) as shown in formula 1 by chiral resolution of intermediate 0 (6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol) as shown in formula 1, and to prepare intermediate 1 ((R)-6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol) as shown in formula 12 (amino-protected 4-(2-aminoethyl)phenyl) The intermediate 3 ((R)-2-(4-(ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide) as shown in Formula 1 is subjected to reductive amination, and the protecting group is deprotected to obtain the intermediate 4 ((R)-N-ethyl-2-(4-(ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide) as shown in Formula 1, and finally the intermediate 3 ((R)-2-(4-(ethyl(2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-5-methoxyphenyl)amino)methyl)phenyl)acetamide) as shown in Formula 1 is subjected to reductive amination with acetaldehyde to obtain the target compound as shown in Formula I, i.e., elastomeric. The intermediate 0 shown in Formula 1 is prepared by using the intermediate 5 shown in Formula 1 (6-hydroxy-3,4-dihydronaphthalene-2(1H)-one) as the starting material to undergo a substitution reaction with a benzyl halide to obtain the intermediate 6 shown in Formula 1 (6-(benzyloxy)-3,4-dihydronaphthalene-2(1H)-one), which is reduced under the action of a reducing agent to obtain the intermediate 7 shown in Formula 1 (6-(benzyloxy)-1,2,3,4-tetrahydronaphthalene-2-ol), which is then halogenated, boronized, and reacted with the intermediate 5 as the starting material to obtain the intermediate 7 shown in Formula 1 (6-(benzyloxy)-1,2,3,4-tetrahydronaphthalene-2-ol). The intermediate 21 (2-(6-(benzyloxy)-1,2,3,4-tetrahydronaphthalene-2-yl)-N-ethyl-5-methoxyaniline) is obtained by catalysis and Suzuki coupling, respectively, and the intermediate 0 is obtained by debenzylation.

[0012] The synthetic route of CN117229157A:

[0013]

[0014] The synthetic route of CN117229156A:

[0015]

[0016] However, the preparation process of elastomeric described in the above invention still does not bypass chiral resolution, the yield is low, and the cost cannot be effectively controlled. Summary of the invention

[0017] In order to solve the defects of the existing methods, such as the overall process steps are complicated and lengthy, the yield is low, and the cost is high, the present invention provides a method for preparing elastomeric hydrochloride. The present invention uses an initial raw material 1 (such as 6-bromo-7,8-dihydronaphthalene-2-ol) with exposed phenolic hydroxyl groups or protected by different protecting groups and biboric acid pinacol ester to react under the action of a palladium catalyst to obtain a borate ester active intermediate 2, which is coupled with a compound 3 (2-bromo-5-methoxyaniline) under the action of a base and a noble metal catalyst to obtain a corresponding hydroxyl-protected intermediate as shown in formula 4, which is then subjected to pressure hydrogenation with a catalyst again, and an intermediate with a target configuration as shown in formula 5 is obtained by asymmetric chiral hydrogenation. The intermediate is subjected to substitution or reductive amination to obtain an intermediate as shown in formula 6, which is further subjected to nucleophilic substitution with intermediate 7 to obtain an intermediate as shown in formula 8, and the protecting groups of the amino group and the phenolic hydroxyl group of the intermediate as shown in formula 8 are deprotected to obtain the target product I, i.e., elastomeric hydrochloride. The present invention bypasses the chiral resolution (a key step affecting cost and yield) step in the existing preparation technology, and introduces chiral groups through asymmetric hydrogenation, thereby greatly improving the yield and significantly reducing the production cost. At the same time, a breakthrough innovation is made in the synthesis route, shortening the cumbersome and lengthy synthesis steps in the original process, and the post-processing is simpler and more controllable.

[0018] Another object of the present invention is to provide an intermediate for preparing elastomeric hydrochloride.

[0019] In order to achieve the above object, the present invention adopts the following technical solutions:

[0020] The present invention provides a method for preparing elastomeric hydrochloride, the preparation method comprising

[0021] 1) reacting an initial raw material as shown in Formula 1 with a naked phenolic hydroxyl group or one protected by different protecting groups with biboric acid pinacol ester under the action of a palladium catalyst to obtain a borate ester active intermediate as shown in Formula 2;

[0022] 2) The intermediate of formula 2 and the compound of formula 3 undergo a coupling reaction under the action of a base and a noble metal catalyst to obtain the corresponding hydroxyl-protected intermediate of formula 4;

[0023] 3) The intermediate shown in Formula 4 is subjected to pressure hydrogenation with a catalyst to obtain the target configuration intermediate shown in Formula 5 by asymmetric chiral hydrogenation, and the intermediate shown in Formula 6 is obtained by substitution or reductive amination;

[0024] 4) the intermediate shown in Formula 6 undergoes nucleophilic substitution with the intermediate shown in Formula 7 to obtain the intermediate shown in Formula 8;

[0025] 5) deprotecting the protecting groups of the amino group and the phenolic hydroxyl group of the intermediate as shown in Formula 8 to obtain the target product, i.e., elastomeric hydrochloride, as shown in Formula I;

[0026] Wherein, the general structure of the substance shown in Formula 1 is as follows:

[0027] The general structure of the substance shown in Formula 2 is as follows:

[0028] The structural formula of the substance shown in Formula 3 is as follows:

[0029] The general structure of the substance shown in Formula 4 is as follows:

[0030] The general structure of the substance shown in Formula 5 is as follows:

[0031] The general structure of the substance shown in Formula 6 is as follows:

[0032] The general structure of the substance shown in Formula 7 is as follows:

[0033] The general structure of the substance shown in Formula 8 is as follows:

[0034] The structural formula of the substance shown in Formula I is as follows:

[0035] Wherein, R1 includes -TBDPS, -TMS, -TES, -TBDMS, -TBS, -TIPS, -MOM, -BOM, -SEM, -Piv, -i-PrCO, -CH3, -Bn, -PMB or -H; R2 includes -Boc, -Ac, -Fmoc, -Tos, -Teoc, -PMB, -Trt or -Bn; X includes -I, -Br, -Cl, -OMs, -OTs or -OTf.

[0036] As a preferred embodiment of the present invention, the preparation method of the substance shown in Formula 7 is: the starting material shown in Formula 9 is reduced in two steps to obtain an intermediate shown in Formula 10 and an intermediate shown in Formula 11, and then the amino group is protected to obtain an intermediate shown in Formula 12 with different amino group protections, and finally the hydroxyl group is replaced to obtain an intermediate shown in Formula 7 with different leaving groups;

[0037] Wherein, the substance structural formula shown in formula 9 is as follows:

[0038] The structural formula of the substance shown in formula 10 is as follows:

[0039] The structural formula of the substance shown in Formula 11 is as follows:

[0040] The structural formula of the substance shown in formula 12 is as follows:

[0041] As a preferred embodiment of the present invention, the noble metal catalyst includes tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride or bis(tri-tert-butylphosphine)palladium; the base includes KOAc, NaOAc, KHCO3 or NaHCO3.

[0042] As a preferred embodiment of the present invention, in the preparation of the intermediate shown in formula 4, the temperature of the first stage is controlled at 70-85°C, the temperature of the second stage is controlled at 70-85°C, and the transition temperature from the first stage to the second stage is controlled at 10-30°C.

[0043] As a preferred embodiment of the present invention, in the preparation of the intermediate shown in formula 4, the ligands used include triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, XantpHos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), BINAP (2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl) or 2,2'-bipyridine.

[0044] As a preferred embodiment of the present invention, in the preparation of the intermediate shown in Formula 5, the catalyst used is composed of a rare metal catalyst and a ligand, wherein the rare metal catalyst includes [(R)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl](p-isopropyltoluene) dichlororuthenium (II), diacetate [(S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium (II), chloro [(S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole](p-cymene) chloride ruthenium (II) ), (-)-1,2-bis[(2R,5R)-2,5-diethylphosphino]benzene(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) chloride dimer or bis(dicyclopentadiene)rhodiumtetrafluoroborate; the ligands used include (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, (4S)-tert-butyl-2-[2-(diphenylphosphino)phenyl]-4,5-dihydrooxazole or (S)-1-[(RP)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine.

[0045] As a preferred embodiment of the present invention, when the intermediate shown in Formula 6 is obtained by substitution reaction, the nucleophilic reagent includes iodoethane, bromoethane or diethyl sulfate, the base used includes potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate or sodium acetate, and the reaction solvent includes 1,4-dioxane, toluene, DMF, DMSO, tetrahydrofuran or acetonitrile;

[0046] When the intermediate of formula 6 is obtained by reductive amination, the reducing agent used includes sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, and the solvent used includes tetrahydrofuran, methanol, ethanol, 1,4-dioxane or dichloromethane.

[0047] As a preferred embodiment of the present invention, after the chiral center is introduced, a chiral purification step is performed on any one of the intermediates shown in Formula 5, the intermediates shown in Formula 6, the intermediates shown in Formula 8 or the substances shown in Formula I, and the enantiomer content is increased to more than 99.9% by chiral separation purification; the chiral separation reagent used is a (+) or (-) chiral acid, including aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, camphor acid, 10-camphorsulfonic acid, trans-1 , 2-cyclohexanedicarboxylic acid, dibenzoyl-tartaric acid, di-p-toluoyl-tartaric acid, N-(3,5-dinitrobenzoyl)-α-phenylglycine, diacetyl-tartaric anhydride, diacetyl-tartaric acid, glutamic acid, malic acid, mandelic acid, N-(α-methylbenzyl)-o-aminobenzoic acid, 2-(6-methoxy-2-naphthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof; the solvent used includes one or a combination of dichloromethane, ethyl acetate, ethanol, methanol, acetonitrile, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran.

[0048] As a preferred embodiment of the present invention, in the preparation of the intermediate shown in formula 11, the reducing agent used includes Raney nickel, sodium borohydride, borane, LiAlH4, diisobutylaluminum hydride, sodium triacetoxyborohydride or sodium cyanoborohydride;

[0049] In the preparation of the intermediate shown in formula 12, the systems for introducing the protective amino group include Boc2O / base / solvent, sodium acetate / acetic anhydride / solvent, Tos-Cl / Et3N, Teoc-Cl / base / solvent, wherein the base used includes DIPEA, Et3N, NaOH, NaHCO3 or Na2CO3.

[0050] As a preferred embodiment of the present invention, in the intermediate shown in Formula 7, the hydroxyl group is substituted by introducing a leaving group, and the system for introducing the leaving group includes Ms-Cl / base / solvent, Ts-Cl / base / solvent, Tf2O / base / solvent, Br4C / PpH3 / solvent, Cl4C / PpH3 / solvent or I / PpH3 / solvent, wherein the base used includes DIPEA, Et3N or pyridine, and the solvent used includes dichloromethane, tetrahydrofuran or 1,4-dioxane.

[0051] Finally, the present invention provides an intermediate for preparing elastomeric hydrochloride, wherein the intermediate includes: the structural formula of the substance shown in formula 1-1 is as follows: The structural formula of the substance shown in Formula 1-2 is as follows: The structural formula of the intermediate shown in Formula 6-1 is as follows: The structural formula of the intermediate shown in Formula 7-1 is as follows: The structural formula of the intermediate shown in Formula 7-2 is as follows: The structural formula of the intermediate shown in Formula 7-3 is as follows:

[0052] The structural formula of the intermediate shown in formula 8-1 is as follows: The structural formula of the intermediate shown in formula 8-2 is as follows: The structural formula of the intermediate shown in formula 8-3 is as follows: The structural formula of the intermediate shown in formula 8-4 is as follows: Compared with the prior art, the present invention has the following beneficial effects:

[0053] 1) The present invention bypasses the chiral resolution (a key step affecting cost and yield) in the existing preparation technology, and introduces chiral groups through asymmetric hydrogenation, which greatly improves the yield and thus significantly reduces the production cost.

[0054] 2) The present invention has made a breakthrough innovation in the synthesis route, shortening the cumbersome and lengthy synthesis steps in the original process, and the post-processing is simpler and more controllable.

[0055] 3) The synthesis route of the present invention is simple, the raw material cost is low, it is easy to obtain, the post-treatment is simple and controllable, and the yield is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 It is the NMR spectrum of the intermediate shown in formula 4.

[0057] Figure 2 It is the NMR spectrum of the intermediate shown in formula 5-1.

[0058] Figure 3 It is the NMR spectrum of the intermediate shown in Formula 6.

[0059] Figure 4 It is the NMR spectrum of the intermediate shown in formula 7-1.

[0060] Figure 5 It is the NMR spectrum of the intermediate shown in formula 8-1.

[0061] Figure 6 It is the NMR spectrum of the compound shown in Formula I.

[0062] Figure 7 It is the NMR spectrum of the intermediate shown in formula 10.

[0063] Figure 8 It is the NMR spectrum of the intermediate shown in formula 11.

[0064] Fig. 9 It is the NMR spectrum of the intermediate shown in formula 12.

[0065] Fig.10 It is the NMR spectrum of the intermediate shown in formula 14.

[0066] Fig.11 It is a graph of the enantiomeric content of the intermediate represented by formula 5-1.

[0067] Fig.12 is a graph showing the enantiomeric content of the compound represented by Formula I. DETAILED DESCRIPTION

[0068] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0069] The invention provides a method for preparing elastomeric hydrochloride. The method comprises the following steps: reacting an initial raw material as shown in formula 1 with a naked phenolic hydroxyl group or a raw material protected by different protecting groups with biboric acid pinacol ester under the action of a palladium catalyst to obtain a borate ester active intermediate as shown in formula 2; performing a coupling reaction with a compound as shown in formula 3 under the action of a base and a noble metal catalyst to obtain a corresponding hydroxyl-protected intermediate as shown in formula 4; performing pressure hydrogenation with a catalyst again to obtain a target configuration intermediate as shown in formula 5 through asymmetric chiral hydrogenation; obtaining an intermediate as shown in formula 6 through substitution or reductive amination; further performing nucleophilic substitution with an intermediate as shown in formula 7 to obtain an intermediate as shown in formula 8; and deprotecting the protecting groups of the amino group and the phenolic hydroxyl group of the intermediate as shown in formula 8 to obtain a target product as shown in formula I, i.e. elastomeric hydrochloride.

[0070] The synthetic route of the present invention is as follows:

[0071]

[0072] In the present invention, the preparation method of the intermediate shown in Formula 7 is as follows: the starting material shown in Formula 9 is reduced in two steps to obtain the intermediate shown in Formula 10 and the intermediate shown in Formula 11, and then the amino group is protected to obtain the intermediate shown in Formula 12 with different amino group protections, and finally the hydroxyl group is substituted to obtain the intermediate shown in Formula 7 with different leaving groups.

[0073] The synthetic route of the intermediate shown in Formula 7 is as follows:

[0074]

[0075] In the above-mentioned preparation method of elastostat, the intermediate as shown in Formula 1 includes an unprotected group, that is, R1 includes -H.

[0076] In the above-mentioned preparation method of elastostat, the phenolic hydroxyl protecting group R1 includes -TBDPS, -TMS, -TES, -TBDMS, -TBS, -TIPS, -MOM, -BOM, -SEM, -Piv, -i-PrCO, -CH3, -Bn or -PMB.

[0077] In the above-mentioned preparation method of elastostat, the amino protecting group R2 includes -Boc, -Ac, -Fmoc, -Tos, -Teoc, -PMB, -Trt or -Bn.

[0078] In the above-mentioned preparation method of elastostat, the leaving group X of the intermediate represented by Formula 7 includes -I, -Br, -Cl, -OMs, -OTs or -OTf.

[0079] In the preparation of the intermediate shown in Formula 1 - the intermediate shown in Formula 4, the precious metal catalyst used includes tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride or bis(tri-tert-butylphosphine)palladium, etc., and bis(tri-tert-butylphosphine)palladium dichloride is preferred in the present invention.

[0080] In the preparation of the intermediate shown in the above formula 1 - the intermediate shown in the above formula 4, the ligands used include triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, XantpHos (4,5-bis-diphenylphosphine-9,9-dimethylxanthene), BINAP (2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl or 2,2'-bipyridine, and tri-tert-butylphosphine tetrafluoroborate is preferred in the present invention.

[0081] In the preparation of the intermediates represented by Formula 1 to the intermediates represented by Formula 4, the base used includes KOAc, NaOAc, KHCO3 or NaHCO3.

[0082] In the preparation of the intermediate shown in Formula 1 - the intermediate shown in Formula 4, the temperature of the first stage is controlled at 70-85°C, and the temperature of the second stage is controlled at 70-85°C. The reaction temperatures of both stages are preferably 80-85°C.

[0083] In the preparation of the intermediate shown in Formula 1 - the intermediate shown in Formula 4, the transition temperature from the first stage to the second stage is controlled at 10-30°C, preferably 15-20°C;

[0084] In the preparation of the intermediates shown in Formula 1 and Formula 4, the solvents used in the reaction include DME (ethylene glycol dimethyl ether), 1,4-dioxane, toluene, DMF, DMSO, ethanol, methanol and water, either alone or in a mixed system. DME is preferred in the first stage of the reaction, and a mixed system of DME and water is preferred in the second stage of the reaction.

[0085] In the preparation of the intermediate shown in Formula 4 - the intermediate shown in Formula 5, the catalyst used is mainly composed of a rare metal catalyst and a ligand, wherein the rare metal catalyst includes [(R)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl](p-isopropyltoluene) dichlororuthenium (II), diacetate [(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium (II), chloro [(S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole](p-cymene) chloride ruthenium (II), (-)-1,2-bis[(2R,5R)-2,5-diethylphosphine]benzene (1,5-cyclooctadiene)rhodium (I) tetrafluoroborate, bis(1,5-cyclooctadiene)iridium (I) chloride dimer or bis(dicyclopentadiene)rhodium tetrafluoroborate, preferably bis(1,5-cyclooctadiene)iridium (I) chloride dimer in the present invention; the ligand used includes (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, (4S)-tert-butyl-2-[2-(diphenylphosphino)phenyl]-4,5-dihydrooxazole or (S)-1-[(RP)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine, preferably (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline in the present invention.

[0086] In the preparation of the intermediates shown in Formula 4 to the intermediates shown in Formula 5, the solvents used include a single or mixed system of dichloromethane (DCM), dichloroethane (DCE), tetrahydrofuran (THF), methanol, and 1,4-dioxane, and DCM is preferred in the present invention.

[0087] In the preparation of the intermediate shown in Formula 4 - the intermediate shown in Formula 5, the reaction temperature is generally controlled at 25-50°C, and preferably 35-45°C in the present invention.

[0088] In the preparation of the intermediate shown in Formula 4 - the intermediate shown in Formula 5, the hydrogen pressure in the reaction is generally controlled at 0.2-10 MPa, and preferably 4-7 MPa in the present invention.

[0089] In the preparation of the intermediate shown in Formula 5 - the intermediate shown in Formula 6, the reaction can obtain the target product through nucleophilic substitution, and the nucleophilic reagent includes iodoethane, bromoethane or diethyl sulfate, etc.; the base used includes potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate or sodium acetate, etc.; the reaction solvent includes 1,4-dioxane, toluene, DMF, DMSO, tetrahydrofuran or acetonitrile, etc.

[0090] In the preparation of the intermediate shown in Formula 5 - the intermediate shown in Formula 6, the reaction can be carried out by reductive amination with acetaldehyde to obtain the target product, and the reducing agent used includes sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, etc., and the solvent used includes tetrahydrofuran, methanol, ethanol, 1,4-dioxane or dichloromethane, etc.

[0091] In the preparation of the intermediate shown in Formula 6 - the intermediate shown in Formula 8, the base used in the reaction includes potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate or sodium acetate, etc.; the reaction solvent includes 1,4-dioxane, toluene, DMF, DMSO, tetrahydrofuran or acetonitrile, etc.

[0092] In the preparation of the intermediate shown in Formula 8, i.e., the compound shown in Formula I, the present invention mainly obtains the target product by deprotecting different amino and hydroxyl protecting groups, and the deprotecting reagents mainly used include TBAF, TEAF or various reagents containing HCl (e.g., HCl-EtOH solution, HCl-MeOH solution, HCl-EA solution, HCl-1 or 4-dioxane solution, etc.), HBr / AcOH, sodium methoxide, potassium methoxide, sodium hydroxide aqueous solution or potassium hydroxide aqueous solution, etc.

[0093] In the above synthesis of elastomeric, after the introduction of the chiral center, the chiral purification step can occur in any intermediate of Formula 5, Formula 6, Formula 8, or Formula I, whose initial enantiomeric content is 50.0% to 99.9%. The enantiomeric content can be increased to more than 99.9% by chiral resolution and purification.

[0094] Wherein, the chiral resolution reagent used is a (+) or (-) chiral acid, including aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, camphoric acid, 10-camphorsulfonic acid, trans-1,2-cyclohexanedicarboxylic acid, dibenzoyl-tartaric acid, di-p-toluoyl-tartaric acid, N-(3,5-dinitrobenzoyl)-α-phenylglycine, diacetyl-tartaric anhydride, diacetyl-tartaric acid, glutamic acid, malic acid, mandelic acid, N-(α-methylbenzyl)-o-aminobenzoic acid, 2-(6-methoxy-2-naphthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof, and D-(+)-dibenzoyltartaric acid is preferred in the present invention.

[0095] The solvent used includes one or a combination of dichloromethane, ethyl acetate, ethanol, methanol, acetonitrile, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. Acetonitrile and toluene are preferred in the present invention.

[0096] In the preparation of the intermediate shown in Formula 9-the intermediate shown in Formula 11, the present invention mainly obtains the target product by reducing acetaldehyde and amide. The reducing agent used includes Raney nickel, sodium borohydride, borane, LiAlH4, diisobutylaluminum hydride, sodium triacetoxyborohydride or sodium cyanoborohydride, etc.

[0097] In the preparation of the intermediate shown in Formula 11 - the intermediate shown in Formula 12, the present invention mainly protects the amino group, and the conditions for introducing the protecting group include Boc2O / base / solvent, sodium acetate / acetic anhydride / solvent, Tos-Cl / Et3N, Teoc-Cl / base / solvent, wherein the base used includes DIPEA, Et3N, NaOH, NaHCO3 or Na2CO3, etc.

[0098] In the preparation of the intermediate shown in Formula 12 - the intermediate shown in Formula 7, the present invention mainly introduces a leaving group to the hydroxyl group, and the conditions used include Ms-Cl / base / solvent, Ts-Cl / base / solvent, Tf2O / base / solvent, Br4C / PpH3 / solvent, Cl4C / PpH3 / solvent or I / PpH3 / solvent, wherein the base used includes DIPEA, Et3N or pyridine, and the solvent used includes dichloromethane, tetrahydrofuran or 1,4-dioxane, etc.

[0099] Example 1

[0100] Elastranose hydrochloride was synthesized using 6-bromo-7,8-dihydronaphthalen-2-yl pivalate as the starting material:

[0101] The synthetic route is as follows:

[0102]

[0103] Step 1-Step 2: Add ethylene glycol dimethyl ether (700 mL) into the reaction bottle, add the starting material (100 g, 1.0 eq), B2Pin2 (86.2 g, 1.05 eq), KOAc (79.3 g, 2.5 eq) as shown in Formula 1 at 15-25°C, replace with nitrogen, add PdCl2(PpH3)2 (0.68 g, 0.003 eq), tri-tert-butylphosphine tetrafluoroborate (0.28 g, 0.003 eq), replace with nitrogen, heat to 80-85°C for reaction, confirm that the raw material reaction is complete (converted into the intermediate shown in Formula 2), cool the reaction system to 10-20°C, add the prepared potassium bicarbonate aqueous solution and the raw material (65.2 g, 1.0 eq) as shown in Formula 3, and heat to 80-85°C for reaction until the intermediate shown in Formula 2 is completely reacted. After confirming that the reaction is complete, cool down, add water to crystallize and stir, filter, drain the filter cake, slurry again with ethanol, filter, and dry the filter cake to obtain the target intermediate (6-(2-amino-4-methoxyphenyl)-7,8-dihydronaphthalen-2-yl pivalate) as shown in Formula 4.

[0104] The NMR spectrum of the intermediate shown in formula 4 is shown in Figure 1 , 1 HNMR (400MHz, DMSO-d6) δ7.11 (d, J=8.2Hz, 1H), 6.94–6.88 (m, 2H), 6.85 (dd, J=8.1, 2.5Hz, 1H), 6.54 (d, J=1.7Hz, 1H), 6.31 (d, J =2.6Hz, 1H), 6.17 (dd, J = 8.4, 2.6Hz, 1H), 4.94 (s, 2H), 3.67 (s, 3H), 2.87 (dd, J = 9.2, 6.9Hz, 2H), 2.56–2.47 (m, 2H), 1.30 (s, 9H).

[0105] Step 3: Add dichloromethane (400 mL) and the intermediate shown in Formula 4 (100 g, 1.0 eq) into the hydrogenation reactor, add Ir catalyst (complex of bis(1,5-cyclooctadiene)iridium(I) chloride dimer and (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, molar ratio 1:1) (0.44 g, 0.0010 eq), replace the reactor with nitrogen three times, replace it with hydrogen three times, fill the reactor with hydrogen pressure to 5.0-6.0 MPa, and react at 40°C until the raw material disappears. The temperature was cooled to room temperature, the reaction solution was filtered, the dichloromethane was concentrated, and finally slurried with an ethyl acetate / n-heptane mixture system, filtered, and the filter cake was dried to obtain the target intermediate ((R)-6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl neopentanoate) as shown in Formula 5-1, with a yield of 93.6% and an enantiomeric content of 97.0%.

[0106] The NMR spectrum of the intermediate shown in formula 5-1 is shown in Figure 2 , 1 HNMR (400MHz, DMSO-d6) δ7.10 (d, J=8.1Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 6.83–6.77 (m, 2H), 6.25 (d, J=2.6Hz, 1H), 6.13 (dd, J=8.4, 2.6Hz, 1H) , 4.96 (s, 2H), 3.64 (s, 3H), 3.01–2.79 (m, 4H), 2.64 (dd, J=17.1, 12.3Hz, 1H), 1.95–1.87 (m, 1H), 1.75 (dd, J=12.1, 5.2Hz, 1H), 1.29 (s, 9H).

[0107] Step 4: In this step, the intermediate shown in Formula 6 can be prepared by two methods:

[0108] Method 1: Add the intermediate (100 g, 1.0 eq) shown in Formula 5-1 to a reaction bottle, add DMF (1000 mL), sodium carbonate (59.4 g, 2.0 eq), iodoethane (65.4 g, 1.5 eq), and heat to 65-70°C for reaction until the raw materials react completely. Cool to room temperature, add water, solid precipitates, filter, and slurry the filter cake with a mixture of ethyl acetate / n-heptane, filter, and dry the filter cake to obtain the target intermediate ((R)-6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl neopentanoate) shown in Formula 6.

[0109] Method 2: The obtained intermediate (100 g, 1.0 eq) as shown in Formula 5-1 is added to a reaction bottle, THF (500 mL) and acetaldehyde (18.5 g, 1.5 eq) are added, and the mixture is stirred at 20-25° C. for more than or equal to 6 h, and sodium triacetoxyborohydride (89.0 g, 1.5 eq) is added to continue the reaction until the raw materials are completely reacted. The reaction system is adjusted to pH 8 with an aqueous NaOH solution and an aqueous NaHCO3 solution, and the solution is allowed to stand for separation. The organic phase is vacuum concentrated to a viscous state, and finally slurried with an ethyl acetate / n-heptane system, filtered, and the filter cake is dried to obtain the target intermediate ((R)-6-(2-(ethylamino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl neopentanoate) as shown in Formula 6.

[0110] The NMR spectrum of the intermediate shown in Formula 6 is shown in Figure 3 , 1 HNMR (400MHz, DMSO-d6) δ7.09 (d, J=8.2Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.83–6.77( m, 2H), 6.15 (dd, J=8.4, 2.5Hz, 1H), 6.09 (d, J=2.5Hz, 1H), 5.08 (t, J=5.5Hz, 1H), 3 .68(s, 3H), 3.12–3.04(m, 2H), 3.02–2.80(m, 4H), 2.59(dd, J=16.1, 11.1Hz, 1H), 1 .94–1.86 (m, 1H), 1.81 (td, J=11.5, 5.3Hz, 1H), 1.29 (s, 9H), 1.17 (t, J=7.1Hz, 3H).

[0111] Step 5: Add the intermediate (100 g, 1.0 eq) shown in Formula 6 to a bottle, add DMF (1000 mL), potassium carbonate (72.5 g, 2.0 eq), and the intermediate (94.2 g, 1.05 eq) shown in Formula 7, and react at 50-60°C until the raw materials react completely. Cool to room temperature, add water, and the solid gradually precipitates. Filter, add ethanol to the filter cake for pulping, filter, and dry the filter cake to obtain the target intermediate ((R)-6-(2-((4-(2-(tert-butyloxycarbonyl)(ethyl)amino)ethyl)benzyl)(ethyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-yl neopentanoate) shown in Formula 8.

[0112] The NMR spectrum of the intermediate shown in formula 8 is shown in Figure 5 , 1HNMR (400MHz, DMSO-d6) δ7.11 (t, J=7.6Hz, 3H), 7.00 (dd, J=8.0, 5.0Hz, 3H), 6.79–6.73 (m, 3H ), 6.64 (dd, J=8.6, 2.6Hz, 1H), 3.95–3.90 (m, 2H), 3.67 (s, 3H), 3.61–3.50 (m, 1H), 3.22 (dd, J= 8.6, 6.5Hz, 2H), 3.06 (s, 2H), 2.88–2.75 (m, 4H), 2.65 (d, J=8.5Hz, 4H), 1.76–1.62 (m, 1H), 1.5 8 (d, J=10.8Hz, 1H), 1.29 (d, J=3.1Hz, 6H), 1.25 (s, 9H), 1.20–1.18 (m, 3H), 0.86–0.78 (m, 6H).

[0113] Step 6: In this step, the target compound shown in formula I can be prepared by three methods:

[0114]

[0115] Method 1:

[0116] The obtained intermediate (100 g, 1.0 eq) as shown in Formula 8 was added to a reaction bottle, ethanol (500 mL) and HCl-EtOH (140 g, 4.0 eq) were added, and the reaction was carried out at 45-50°C. The reaction raw materials disappeared after monitoring by HPLC, and the intermediate as shown in Formula 8-2 was generated; the temperature was raised to 65°C and the reaction was continued until the reaction was complete. The temperature was lowered to 20-25°C, ethyl acetate was added, the temperature was kept stirring for 1 hour, suction filtered, and the filter cake was dried; the dried solid was added to a bottle, methanol was added, the temperature was raised to 65°C, stirred to dissolve, the temperature was lowered for crystallization, ethyl acetate was added, stirring was continued for 2-3 hours, filtered, and the filter cake was dried to obtain the target compound ((R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol hydrochloride) as shown in Formula I.

[0117] Method 2:

[0118] The obtained intermediate (100 g, 1.0 eq) as shown in Formula 8 was added to a reaction bottle, and a methanol solution of sodium methoxide (117 mL) was added. The reaction was carried out at 40°C. The reaction raw materials disappeared after monitoring by HPLC, and the intermediate as shown in Formula 8-5 was generated. After the reaction was completed, water was added, and the pH was adjusted to 7 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was concentrated to dryness in vacuo. Ethanol (500 mL) and HCl-EtOH (70 g, 2.0 eq) were added, and the temperature was raised to 65°C, and the reaction was continued until the reaction was complete. The temperature was reduced to 20-25°C, ethyl acetate was added, and the mixture was stirred for 1 h at room temperature, filtered, and the filter cake was dried. The dried solid was added to a bottle, methanol was added, the temperature was raised to 65°C, and the mixture was stirred to dissolve. The temperature was lowered to crystallize, and ethyl acetate was added. The mixture was stirred for 2-3 h, filtered, and the filter cake was dried to obtain the target compound as shown in Formula I.

[0119] Method 3:

[0120] The obtained intermediate (100 g, 1.0 eq) as shown in Formula 8 was added to a reaction bottle, and ethanol (500 mL) and HCl-EtOH (70.0 g, 2.0 eq) were added, and the reaction was carried out at 45-50°C. The reaction raw materials disappeared after monitoring by HPLC, and the intermediate shown in Formula 8-2 was generated. After the reaction was completed, it was diluted with water, and the pH was adjusted to 8 with an aqueous NaHCO3 solution. The mixture was extracted with ethyl acetate and concentrated to dryness. A methanol solution of sodium methoxide (117 mL) was added, and the reaction was carried out at 40°C. The reaction raw materials disappeared after monitoring by HPLC. After the reaction was completed, water was added, the pH was adjusted to 7 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic phase was concentrated in vacuo to dryness, ethanol (500 mL) and HCl-EtOH (70 g, 2.0 eq) were added, and the mixture was stirred for crystallization. Ethyl acetate was added, and the stirring was continued for 2-3 h. The mixture was filtered, and the filter cake was dried to obtain the target compound shown in Formula I.

[0121] 1 H NMR(500MHz,DMSO-d6)δ9.18(d,J=82.0Hz,2H),7.56(s,1H),7.32–7.13(m,4H),7.10(d,J=7 .7Hz,1H),7.02(d,J=8.5Hz,1H),6.80(d,J=8.0Hz,1H),6.51(t,J=15.4Hz,2H),4.78(dt,J= 33.6,12.1Hz,2H),3.96–3.80(m,5H),3.32(s,1H),3.15–2.81(m,8H),2.57(dd,J=24.7,11. 8Hz, 2H), 1.61 (s, 1H), 1.22 (t, J = 7.2Hz, 3H), 1.00 (t, J = 7.0Hz, 3H), 0.18 (d, J = 12.0Hz, 1H).

[0122] The NMR spectrum of the target compound shown in Formula I is shown in Figure 6 .

[0123] After the intermediate shown in Formula 8-2 or the intermediate shown in Formula 8-5 is prepared, a chiral purification step can be performed before continuing to the next step of the reaction; or the target compound shown in Formula I can be finally subjected to a chiral purification step.

[0124] The important intermediate 7-1 was synthesized using N-ethyl-2-(4-formylphenyl)acetamide as the starting material. The synthetic route is as follows:

[0125]

[0126] Step 1-Step 2: This step can be synthesized in two ways as shown in Formula 12.

[0127] Method 1: Add the compound (15.0 g, 1.0 eq) shown in Formula 9 to a reactor, add methanol (90 mL) and Raney nickel (10 g, 1.5 eq), install the reactor, replace with nitrogen, replace with hydrogen, fill with hydrogen pressure of 0.5-0.6 MPa, and react until the raw material disappears completely. Filter the reaction solution, and concentrate the filtrate to dryness in vacuo to obtain the intermediate (N-ethyl-2-(4-(hydroxymethyl)phenyl)acetamide) shown in Formula 10.

[0128] The NMR spectrum of the intermediate shown in formula 10 is shown in Figure 7 , 1 HNMR (400MHz, DMSO-d6) δ8.00 (d, J=5.9Hz, 1H), 7.25–7.16 (m, 4H), 5.12 (t, J=5.7Hz, 1H), 4.4 5 (d, J=5.7Hz, 2H), 3.34 (d, J=1.3Hz, 2H), 3.05 (qd, J=7.2, 5.5Hz, 2H), 1.00 (t, J=7.2Hz, 3H).

[0129] Add THF (90 mL) to the reaction bottle, cool to 0-5°C, add sodium borohydride (2.6 g, 3.0 eq), add the intermediate (4.5 g, 1.0 eq) shown in Formula 10, control the temperature at 0-10°C, add boron trifluoride ether complex (8.3 g, 2.5 eq), and react at 65°C until the reaction is complete.

[0130] Post-treatment: After the reaction is completed, cool to 0-5°C, control the temperature at 0-10°C, add concentrated hydrochloric acid and water to quench, distill the organic solvent completely, cool to room temperature, extract the aqueous phase with ethyl acetate, discard the organic phase, adjust the pH to alkaline with 10% NaOH aqueous solution, extract the alkaline aqueous phase with ethyl acetate, combine the organic phases and concentrate in vacuo to dryness to obtain the intermediate ((4-(2-(ethylamino)ethyl)phenyl)methanol) as shown in Formula 11.

[0131] Method 2: Add THF (90 mL) to the reaction bottle, cool to 0-5°C, add sodium borohydride (3.0 eq), add the compound shown in Formula 9 (1.0 eq), warm to room temperature, and monitor by HPLC that the raw material is completely converted into the intermediate shown in Formula 10; reduce the reaction system to 0-5°C, control the temperature at 0-10°C, add boron trifluoride ether complex (2.5 eq), and react at 65°C until the reaction is complete.

[0132] Post-treatment: After the reaction is completed, cool to 0-5°C, control the temperature at 0-10°C, add concentrated hydrochloric acid and water to quench, distill the organic solvent completely, cool to room temperature, extract the aqueous phase with ethyl acetate, discard the organic phase, adjust the pH to alkaline with 10% NaOH aqueous solution, extract the alkaline aqueous phase with ethyl acetate, combine the organic phases and concentrate in vacuo to dryness to obtain the intermediate ((4-(2-(ethylamino)ethyl)phenyl)methanol) as shown in Formula 11.

[0133] The NMR spectrum of the intermediate shown in formula 11 is shown in Figure 8 , 1 HNMR (500MHz, DMSO-d6) δ9.17–9.08 (m, 1H), 7.31–7.16 (m, 4H), 5.19 (s, 1H) , 4.47 (s, 2H), 3.10–3.04 (m, 2H), 3.00–2.90 (m, 4H), 1.22 (t, J=7.3Hz, 3H).

[0134] Step 3: Add the intermediate (4.0 g, 1.0 eq) shown in Formula 11 to a reaction bottle, add THF (40 mL), Boc2O (9.7 g, 2.0 eq), DIPEA (7.2 g, 2.5 eq), and stir at room temperature until the reaction is complete. After the reaction is completed, vacuum concentrate to remove THF, add water, extract twice with ethyl acetate, combine the organic phases, vacuum concentrate, and separate and purify by column chromatography to obtain the intermediate (tert-butyl (4-(hydroxymethyl)phenethyl)carbamate) shown in Formula 12.

[0135] The NMR spectrum of the intermediate shown in formula 12 is shown in Fig. 9 , 1HNMR (400MHz, DMSO-d6) δ7.24 (d, J=7.9Hz, 2H), 7.15 (d, J=7.8Hz, 2H), 5.13 (t, J=5.7Hz, 1H), 4.47 (d, J=5.7Hz, 2H), 3. 30 (dd, J=8.8, 6.5Hz, 2H), 3.14 (d, J=7.0Hz, 2H), 2.74 (dd, J=8.8, 6.4Hz, 2H), 1.44–1.31 (m, 9H), 1.01 (t, J=7.1Hz, 3H).

[0136] Step 4: Add the intermediate (1.0 g, 1.0 eq) shown in Formula 12 to the reaction bottle, add DCM (10 mL), lower the internal temperature to 0-5°C, add PpH3 (1.1 g, 1.2 eq) and CBr4 (1.4 g, 1.2 eq), and keep warm to react until the raw materials disappear. After the reaction is completed, vacuum concentrate, column chromatography separation and purification are performed to obtain the target intermediate shown in Formula 7-1.

[0137] The NMR spectrum of the intermediate shown in formula 7-1 is shown in Figure 4 , 1 HNMR (400MHz, DMSO-d6) δ7.37 (d, J=7.9Hz, 2H), 7.19 (d, J=7.7Hz, 2H), 4.68 (s, 2H), 3.32 (dd, J=8.5, 6.5H z, 2H), 3.15 (t, J=7.6Hz, 2H), 2.75 (dd, J=8.5, 6.5Hz, 2H), 1.35 (d, J=15.1Hz, 9H), 1.00 (t, J=7.0Hz, 3H).

[0138] Example 2

[0139] Elastranose hydrochloride is synthesized using 4-bromo-3-nitroanisole as a raw material. The synthesis route is as follows:

[0140]

[0141] Step 1: Add the intermediate (10.0 g, 1.0 eq) as shown in Formula 6-1 to a bottle, add DMF (10 mL), potassium carbonate (5.2 g, 2.0 eq), and the intermediate (6.7 g, 1.05 eq) as shown in Formula 7-1, and react at 50-60°C until the raw materials react completely. Cool to room temperature, add water, and the solid gradually precipitates. Filter, add ethanol to the filter cake, filtrate, and dry the filter cake to obtain the target intermediate as shown in Formula 8-3.

[0142] The NMR spectrum of the intermediate shown in formula 8-3 is shown in Fig.10 , 1HNMR (400MHz, DMSO-d6) δ7.69 (dt, J=8.1, 1.8Hz, 4H), 7.48–7.38 (m, 6H), 7.10 (dd, J=8.3, 3.9Hz, 3H), 7.02 (d, J=7.8Hz, 2H), 6.78 ( d, J=2.7Hz, 1H), 6.72 (d, J=8.4Hz, 1H), 6.64 (dd, J=8.6, 2.6Hz, 1H), 6.57 (d, J=2.6Hz, 1H), 6.41 (dd, J=8.3, 2.6Hz, 1H), 3.94 (d, J= 2.5Hz, 2H), 3.69 (s, 3H), 3.57–3.45 (m, 1H), 3.26 (t, J=7.6Hz, 2H), 3.10 (s, 2H), 2.85 (q, J=7.0Hz, 2H), 2.67 (s, 4H), 2.55 (d, J=11. 2Hz, 2H), 1.63 (qd, J=12.1, 5.7Hz, 1H), 1.52 (s, 1H), 1.40–1.28 (m, 9H), 1.04 (s, 9H), 0.95 (t, J=7.1Hz, 3H), 0.84 (t, J=7.0Hz, 3H).

[0143] Step 2: In this step, the compound shown in Formula I can be synthesized by the following two methods. The synthesis route is as follows:

[0144]

[0145] Method 1: Add the intermediate (5.0 g, 1.0 eq) shown in Formula 8-3 to a reaction bottle, add ethanol (40 mL) and HCl-EtOH (5.5 g, 4.0 eq), react at 45-50°C, monitor the disappearance of the reaction raw materials by HPLC, and generate the intermediate shown in Formula 8-4; raise the temperature to 65°C and continue the reaction until the reaction is complete. Lower the temperature to 20-25°C, add ethyl acetate, stir for 1 hour, filter by suction, and dry the filter cake; add the dried solid to a bottle, add methanol, raise the temperature to 65°C, stir to dissolve, cool and crystallize, add ethyl acetate, continue stirring for 2-3 hours, filter, and dry the filter cake to obtain the target compound ((R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol hydrochloride) shown in Formula I.

[0146] Method 2: Add the intermediate (5.0 g, 1.0 eq) obtained as shown in Formula 8-3 to a reaction bottle, add THF, add TBAF (10 mL, 1.5 eq) dropwise under stirring, and stir at room temperature until the raw material disappears. Concentrate in vacuo until viscous, add ethyl acetate to dissolve, wash three times with water, collect the organic phase, concentrate until viscous, add ethanol to drag, and finally obtain an ethanol solution of the intermediate shown in Formula 8-5;

[0147] To the obtained ethanol solution of the intermediate shown in Formula 8-5, add HCl-EtOH (5.5 g, 4.0 eq), react at 45-50°C, and monitor the disappearance of the reaction raw materials by HPLC. Reduce the temperature to 20-25°C, add ethyl acetate, stir for 1 hour, filter with suction, and dry the filter cake; add the dried solid to a bottle, add methanol, heat to 65°C, stir to dissolve, cool and crystallize, add ethyl acetate, continue stirring for 2-3 hours, filter, and dry the filter cake to obtain the target compound shown in Formula I ((R)-6-(2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol hydrochloride).

[0148] After the intermediate shown in Formula 8-4 is prepared, a chiral purification step can be performed before proceeding to the next step; or the target compound shown in Formula I can be finally subjected to a chiral purification step.

[0149] Example 3

[0150] The chiral purification of the compound represented by formula I is as follows:

[0151]

[0152] The obtained compound as shown in Formula I is added to a reaction flask, and the pH is adjusted to about 8 with aqueous sodium hydroxide solution and aqueous sodium bicarbonate solution. After extraction with ethyl acetate, the ethyl acetate phase is concentrated to dryness to obtain an off-white solid, and the solid is dried. The dried solid (the free compound as shown in Formula I) (30.0 g, 1.0 eq) is added to a reaction flask, and a mixed solvent of acetonitrile and toluene is added. The temperature is raised and stirred until dissolved, and (+)-DBTA (23.0 g, 0.98 eq) is added. The temperature is controlled to 75-80°C and stirred for 1 hour, and the temperature is lowered and stirred to crystallize, and the filter cake is filtered. The enantiomeric content is detected. If the enantiomeric content is ≥99.9%, it is dried. If it is less than 99.9%, the above operation is repeated until the enantiomeric content is ≥99.9%. For the enantiomeric content diagram of the compound shown in Formula I, see Fig.12 .

[0153] Example 4

[0154] The chiral purification of the intermediate shown in formula 5-1 is as follows:

[0155]

[0156] Add the intermediate shown in Formula 5-1 (10.0 g, 1.0 eq) to a reaction flask, add a mixed solvent of acetonitrile and toluene, heat and stir until dissolved, and add (+)-DBTA (9.93 g, 0.98 eq). Control the temperature to 75-80°C and stir for 1 hour, cool and stir to crystallize, filter with suction, and test the enantiomer content of the filter cake. If the enantiomer content is ≥99.9%, dry it. If it is less than 99.9%, repeat the above operation until the enantiomer content is ≥99.9%. See the enantiomer content chart of the intermediate shown in Formula 5-1. Fig.11 .

[0157] Example 5

[0158] Chiral purification of the racemic intermediate 5-1: as follows:

[0159]

[0160] Add the racemic intermediate 5-1 (10.0 g, 1.0 eq) to a reaction flask, add a mixed solvent of acetonitrile and toluene, heat and stir until dissolved, add (+)-DBTA (5.23 g, 0.50 eq), control the temperature to 75-80°C and stir for 1 hour, cool and stir to crystallize, filter by suction, and test the enantiomer content of the filter cake. If the enantiomer content is ≥99.9%, dry it. If it is less than 99.9%, repeat the above operation until the enantiomer content is ≥99.9%.

[0161] The above is only a preferred embodiment of the present invention, and is not any formal or substantial limitation of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention. Any technician familiar with this profession, without departing from the spirit and scope of the present invention, can make some changes, modifications and evolutions of the technical content disclosed above, which are equivalent embodiments of the present invention; at the same time, any changes, modifications and evolutions of any equivalent changes made to the above embodiments based on the essential technology of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A method for preparing elastomeric hydrochloride, characterized in that: The preparation method comprises 1) reacting an initial raw material as shown in Formula 1 with a naked phenolic hydroxyl group or one protected by different protecting groups with biboric acid pinacol ester under the action of a palladium catalyst to obtain a borate ester active intermediate as shown in Formula 2; 2) The intermediate of formula 2 and the compound of formula 3 undergo a coupling reaction under the action of a base and a noble metal catalyst to obtain the corresponding hydroxyl-protected intermediate of formula 4; 3) The intermediate shown in Formula 4 is subjected to pressure hydrogenation with a catalyst to obtain the target configuration intermediate shown in Formula 5 by asymmetric chiral hydrogenation, and the intermediate shown in Formula 6 is obtained by substitution or reductive amination; 4) the intermediate shown in formula 6 undergoes nucleophilic substitution with the intermediate shown in formula 7 to obtain the intermediate shown in formula 8; 5) deprotecting the protecting groups of the amino group and the phenolic hydroxyl group of the intermediate as shown in Formula 8 to obtain the target product, i.e., elastomeric hydrochloride, as shown in Formula I; Wherein, the general structure of the substance shown in Formula 1 is as follows: The general structure of the substance shown in Formula 2 is as follows: The structural formula of the substance shown in Formula 3 is as follows: The general structure of the substance shown in Formula 4 is as follows: The general structure of the substance shown in Formula 5 is as follows: The general structure of the substance shown in Formula 6 is as follows: The general structure of the substance shown in Formula 7 is as follows: The general structure of the substance shown in Formula 8 is as follows: The structural formula of the substance shown in Formula I is as follows: Wherein, R1 includes -TBDPS, -TMS, -TES, -TBDMS, -TBS, -TIPS, -MOM, -BOM, -SEM, -Piv, -i-PrCO, -CH3, -Bn, -PMB or -H; R2 includes -Boc, -Ac, -Fmoc, -Tos, -Teoc, -PMB, -Trt or -Bn; X includes -I, -Br, -Cl, -OMs, -OTs or -OTf.

2. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: The preparation method of the substance represented by Formula 7 is as follows: the starting material represented by Formula 9 is reduced in two steps to obtain an intermediate represented by Formula 10 and an intermediate represented by Formula 11, and then the amino group is protected to obtain an intermediate represented by Formula 12 with different amino group protections, and finally the hydroxyl group is substituted to obtain an intermediate represented by Formula 7 with different leaving groups; Among them, the substance structural formula shown in formula 9 is as follows: The structural formula of the substance shown in formula 10 is as follows: The structural formula of the substance shown in Formula 11 is as follows: The structural formula of the substance shown in formula 12 is as follows:

3. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: The noble metal catalyst includes tetrakis(triphenylphosphine)palladium, palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium dichloride or bis(tri-tert-butylphosphine)palladium; the base includes KOAc, NaOAc, KHCO3 or NaHCO3.

4. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: In the preparation of the intermediate shown in formula 4, the temperature of the first stage is controlled at 70-85°C, the temperature of the second stage is controlled at 70-85°C, and the transition temperature from the first stage to the second stage is controlled at 10-30°C.

5. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: In the preparation of the intermediate shown in formula 4, the ligands used include triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine tetrafluoroborate, 4,5-bisdiphenylphosphino-9,9-dimethylxanthene, 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl or 2,2'-bipyridine.

6. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: In the preparation of the intermediate shown in Formula 5, the catalyst used is composed of a rare metal catalyst and a ligand, wherein the rare metal catalyst includes [(R)-(+)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl](p-isopropyltoluene) dichlororuthenium (II), diacetate [(S)-(-)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl]ruthenium (II), chloro [(S)-(-)-5,5'-bis(diphenylphosphine)-4,4'-di-1,3-benzodioxole](p-cymene) chloride ruthenium (II), (-)-1 , 2-bis[(2R,5R)-2,5-diethylphosphino]benzene(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate, bis(1,5-cyclooctadiene)iridium(I) chloride dimer or bis(dicyclopentadiene)rhodiumtetrafluoroborate; the ligands used include (S)-(-)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline, (4S)-tert-butyl-2-[2-(diphenylphosphino)phenyl]-4,5-dihydrooxazole or (S)-1-[(RP)-2-(di-tert-butylphosphino)ferrocenyl]ethylbis(2-methylphenyl)phosphine.

7. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: When the intermediate of Formula 6 is obtained by substitution reaction, the nucleophilic reagent includes iodoethane, bromoethane or diethyl sulfate, the base used includes potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium acetate or sodium acetate, and the reaction solvent includes 1,4-dioxane, toluene, DMF, DMSO, tetrahydrofuran or acetonitrile; When the intermediate of formula 6 is obtained by reductive amination, the reducing agent used includes sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride, and the solvent used includes tetrahydrofuran, methanol, ethanol, 1,4-dioxane or dichloromethane.

8. The method for preparing elastomeric hydrochloride according to claim 1, characterized in that: After the chiral center is introduced, a chiral purification step is performed on any one of the intermediates shown in Formula 5, the intermediates shown in Formula 6, the intermediates shown in Formula 8 or the substances shown in Formula I, and the enantiomer content is increased to more than 99.9% by chiral separation purification; the chiral separation reagent used is a (+) or (-) chiral acid, including aspartic acid, O-acetyl-mandelic acid, cis-2-benzamidocyclohexanecarboxylic acid, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate, camphoric acid, 10-camphorsulfonic acid, trans-1,2-cyclohexane Dicarboxylic acid, dibenzoyl-tartaric acid, di-p-toluoyl-tartaric acid, N-(3,5-dinitrobenzoyl)-α-phenylglycine, diacetyl-tartaric anhydride, diacetyl-tartaric acid, glutamic acid, malic acid, mandelic acid, N-(α-methylbenzyl)-o-aminobenzoic acid, 2-(6-methoxy-2-naphthyl)propionic acid, pyroglutamic acid, quinic acid and tartaric acid or a combination thereof; the solvent used includes one or a combination of dichloromethane, ethyl acetate, ethanol, methanol, acetonitrile, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran.

9. The method for preparing elastomeric hydrochloride according to claim 2, characterized in that: In the preparation of the intermediate shown in formula 11, the reducing agent used includes Raney nickel, sodium borohydride, borane, LiAlH4, diisobutylaluminum hydride, sodium triacetoxyborohydride or sodium cyanoborohydride; In the preparation of the intermediate shown in formula 12, the systems for introducing the protective amino group include Boc2O / base / solvent, sodium acetate / acetic anhydride / solvent, Tos-Cl / Et3N, Teoc-Cl / base / solvent, wherein the base used includes DIPEA, Et3N, NaOH, NaHCO3 or Na2CO3.

10. The method for preparing elastomeric hydrochloride according to claim 2, characterized in that: In the preparation of the intermediate shown in formula 7, the hydroxyl group is replaced by introducing a leaving group. The system for introducing a leaving group includes Ms-Cl / base / solvent, Ts-Cl / base / solvent, Tf2O / base / solvent, Br4C / PPh3 / solvent, Cl4C / PPh3 / solvent or I / PPh3 / solvent, wherein the base used includes DIPEA, Et3N or pyridine, and the solvent used includes dichloromethane, tetrahydrofuran or 1,4-dioxane.

11. An intermediate for preparing elastomeric hydrochloride, characterized in that: The intermediates include: The structural formula of the substance shown in Formula 1-1 is as follows: The structural formula of the substance shown in Formula 1-2 is as follows: The structural formula of the intermediate shown in Formula 6-1 is as follows: The structural formula of the intermediate shown in Formula 7-1 is as follows: The structural formula of the intermediate shown in Formula 7-2 is as follows: The structural formula of the intermediate shown in Formula 7-3 is as follows: The structural formula of the intermediate shown in formula 8-1 is as follows: The structural formula of the intermediate shown in formula 8-2 is as follows: The structural formula of the intermediate shown in formula 8-3 is as follows: The structural formula of the intermediate shown in formula 8-4 is as follows:

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