Method for preparing 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane derivatives

Abstract

The present disclosure relates to a method for preparing a 9-(pyridine-2-yl)-6-oxaspiro[4.5]decane derivative. Specifically, the method comprises reacting a compound A with (1 S ,4 S The preparation reaction of )-4-ethoxy-1,2,3,4-tetrahydro-1-naphthylamine forms an amide compound, which is then reduced to form an oxaspirocyclic derivative. The process has a short process route and a high yield, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing 9-(pyridin-2-yl)-6-oxaspiro[4.5]decane derivatives. Background Art

[0002] (1S,4S)-4-Ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine is a new MOR agonist used to treat moderate to severe pain and was approved for marketing in 2024.

[0003] US2020 / 368309 and other documents report a process of converting a carboxylic acid compound into an aldehyde, reacting the aldehyde with an amine to form an enamine, and reacting under reducing conditions to form the target product (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalene-1-amine.

[0004] . Summary of the invention

[0005] The present disclosure provides a method for preparing compound D or a pharmaceutically acceptable salt thereof.

[0006] , characterized in that the method comprises the step of reacting compound A with compound B in the presence of a condensation reagent to form a compound of formula C, wherein the condensation reagent is selected from one or more of DCC, EDCI, BOP, DMAP, HOBT and EEDQ

[0007] .

[0008] In other embodiments, the condensation reagent is selected from EDCI, EDCI / HOBT, EDCI / DMAP.

[0009] In other embodiments, the condensation reagent is selected from EDCI / HOBT.

[0010] Further, in some embodiments, the molar ratio of compound A to EDCI is 1:0.5-1:5, including 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0 or any value between two numbers.

[0011] In some embodiments, the molar ratio of Compound A to EDCI is 1:1-1:3.

[0012] In some embodiments, the molar ratio of Compound A to EDCI is 1:1-1:2.

[0013] On the other hand, in some embodiments, the molar ratio of Compound A to HOBT is 1:0.5-1:5, including 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0 or any value between two numbers.

[0014] In some embodiments, the molar ratio of Compound A to HOBT is 1:1-1:3.

[0015] In some embodiments, the molar ratio of Compound A to HOBT is 1:1-1:2.

[0016] In other embodiments, the solvent used for the reaction of compound A and compound B is selected from acetonitrile, N-methylpyrrolidone, dichloromethane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0017] In some embodiments, the solvent used for the reaction of compound A and compound B is selected from dichloromethane and tetrahydrofuran.

[0018] In other embodiments, the temperature used for the reaction of compound A and compound B is 20-50°C, including 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C or any value between two numbers.

[0019] In other embodiments, the reaction of compound A and compound B further contains an acid-binding agent, and the acid-binding agent is selected from but not limited to one or more of pyridine, triethylamine, diisopropylethylamine, and triethanolamine.

[0020] In some embodiments, compound A reacts with compound B in the presence of EDCI, HOBT and triethylamine to form compound C, wherein the molar ratio of compound A to EDCI is 1:1-1:3, and the molar ratio of compound A to HOBT is 1:1-1:3.

[0021] Furthermore, the method for preparing compound D or a pharmaceutically acceptable salt thereof further comprises the step of reacting compound C in the presence of a reducing agent to form compound D, wherein the reducing agent is selected from borane dimethyl sulfide,

[0022] .

[0023] In some embodiments, the molar ratio of compound C to the reducing agent is 1:1 to 1:2, including 1:1, 1:1.2, 1:1.4, 1:1.6, 1:1.8, 1:2.0 or any value between two numbers.

[0024] In other embodiments, the method for preparing Compound D or a pharmaceutically acceptable salt thereof comprises the following steps:

[0025] a) Compound A reacts with Compound B in the presence of EDCI, HOBT and triethylamine to form Compound C;

[0026] b) Compound C reacts in the presence of a reducing agent to form Compound D, wherein the reducing agent is selected from borane dimethyl sulfide,

[0027] .

[0028] The present disclosure also provides compound C or a salt thereof .

[0029] On the other hand, the preparation method disclosed in the present invention further comprises one or more steps of filtration, concentration, purification by column chromatography and drying.

[0030] The term "converted" in the present disclosure does not specifically mean that the conversion reaction between two substrates is a single step, but may be a single step or multi-step reaction between two substrates. If the intermediate contains a protecting group, the intermediate is subjected to a step of removing the protecting agent, and then reacts with the corresponding substrate to obtain the corresponding target product.

[0031] The values ​​in this disclosure are instrumental measurements, which have a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the particle size of the active ingredient, the value is the error change after measurement does not exceed plus or minus 10%, can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

[0032] The pharmaceutically acceptable salt of the compound in the present disclosure can be selected from an inorganic pharmaceutically acceptable salt or an organic pharmaceutically acceptable salt, such as a fumarate. In some embodiments, the pharmaceutically acceptable salt of Compound D is selected from a fumarate of Compound D.

[0033] The salt of the compound in the present disclosure can be selected from inorganic salts or organic salts, including "acid" addition salts and "base" addition salts. For example, salts formed by acid-base reaction with a basic group (amino group), the acid including organic acid or inorganic acid.

[0034] In the chemical structures of the compounds disclosed herein, the bond " " indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond" ” can be "or" ", or both "and" "Two configurations.

[0035] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

[0036] HOBT: 1-hydroxybenzotriazole.

[0037] EEDQ: .

[0038] BOP: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

[0039] DCC: N,N'-dicyclohexylcarbodiimide. DETAILED DESCRIPTION

[0040] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0041] The experimental methods in the examples of this disclosure that do not specify specific conditions are usually carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market.

[0042] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm).

[0043] NMR measurements were performed using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvent was deuterated chloroform (CDCl3).

[0044] MS was determined using a Waters Micromass Quattro micro API triple quadrupole mass spectrometer in positive / negative ion mode with a mass scan range of 120-1300.

[0045] HPLC column: YMC-Pack ODS-A (3μm, 4.6 mm x 150 mm)

[0046] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification of thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm. Example 1

[0047]

[0048] Step 1: Add 100 ml (10V) of dichloromethane, 10 g (1 eq, prepared by referring to the method in CN110678453) of compound A, and 6.95 g (1 eq) of compound B to a 250 ml three-necked flask, stir to dissolve, cool to 10-20°C, add 7.35 g (2 eq) of triethylamine and stir for 5-10 min, add 4.91 g (1.2 eq) of HOBT and stir to react for 1 h, slowly add 8.35 g (1.2 eq) of EDCI in batches, and after the addition, heat to 30-40°C and stir to react for 2-3 h. Filter the reaction solution, rinse the filter cake with 5 ml of dichloromethane, drain, collect all the filtrate, add 50 ml (5V) of purified water and wash 3 times, collect all the organic layers, dry with 2.5 g (0.5 eq) of anhydrous sodium sulfate, filter, and concentrate to obtain 14.2 g of compound C (yield 90.01%).

[0049] MS m / z (ESI): 343.5[M+H] + .

[0050] Step 2: Add 142 ml of tetrahydrofuran to a 250 ml three-necked flask and stir to dissolve, then slowly drop it into a tetrahydrofuran solution of borane dimethyl sulfide (2.98 g (1.2 eq) of borane dimethyl sulfide, 10 ml of tetrahydrofuran) and stir to react for 3-4 hours. After the reaction is completed, cool the system to -5-0 °C, add 10 ml of purified water to quench, stir for 1-2 hours, stand for stratification, wash the organic layer twice with 2% sodium chloride solution (2 g of sodium chloride, 10 ml of purified water), stand for stratification, collect the organic layer and dry it with 23 g (0.5 eq) of anhydrous sodium sulfate for 1-2 hours. Filter and concentrate to obtain a concentrated solution, add 71 ml of acetonitrile (5V) to the concentrated solution, cool to -10-0 °C, stir for 1~2 hours, filter, and dry in a vacuum oven at 50 °C to obtain 12.36 g of compound D (yield 90.0%).

[0051] 1 H NMR (400 MHz, d 6-DMSO) 8.52-8.54 (dd, 1H), 7.70-7.74 (d, 1H), 7.44-7.46 (d, 1H), 7.23-7.25 (m, 1H), 7.13-7.20 (m, 4H), 4.26-4.29 (t, 1H), 3.54-3.60 (m, 3H), 3.42-3.53 (m, 2H), 2.41 (d, 1H), 2.30-2.35 (m, 2H), 1.97-2.01(m, 2H), 1.77-1.84 (m, 3H),1.51-1.67 (m, 5H),1.31-1.47 (m, 6H), 1.09-1.12 (t,3H), 0.96-1.00 (m, 1H), 0.60-0.63 (m, 1H). Example 2

[0052]

[0053] In a 250 ml three-necked flask, add 125 ml of isopropanol, 12.3 g of compound D prepared in Example 1 and 3.39 g (1 eq) of fumaric acid, heat to 75-82°C and stir for 1-2 h, cool to 20-30°C, and crystallize. Filter by suction, rinse with isopropanol, and vacuum dry at 50-55°C for 10-12 h to obtain 11.31 g of the target product, fumaric acid compound D (yield 89.0%, HPLC purity 99.8%).

[0054] Example 3: Investigating the effects of different reducing agent conditions on amide reduction

[0055]

[0056] The specific reaction conditions are shown in the following table. Different reduction conditions are used to prepare the yield of compound D.

[0057] reducing agent Compound C: reducing agent (eq.) Reaction solvent Yield Lithium Aluminum Tetrahydride 1.0:1.5 Ether 51.00% Boron trifluoride ethyl etherate and sodium borohydride 1.0:1.7:1.2 Tetrahydrofuran 58.40% Borane dimethyl sulfide 1.0:1.2 Tetrahydrofuran 90.01% Red Aluminum 1.0:2.5 Toluene 47.10%

[0058] From the above table, it can be seen that when borane dimethyl sulfide (1.2 eq) is used as a reducing agent, the yield of compound D is higher for the reduction of compound C, so borane dimethyl sulfide is the optimal reducing agent.

[0059] Example 4: Investigating the effects of different condensation conditions

[0060]

[0061] The specific reaction conditions are shown in the following table. Different condensation conditions are used to prepare the yield of compound C.

[0062] Condensation reagents Compound A: condensing agent (eq.) Reaction solvent Yield DMAP+EDCI 1.0:1.5:1.5 DMAC 71.41% HOBT+EDCI 1.0:1.2:1.2 Dichloromethane 90.00% EDCI 1.0:1.2 DMAC 61.40%

[0063] As can be seen from the above table, HOBT + EDCI as the condensation solvent has the highest yield for compound C and is the optimal condensation reagent.

Claims

1. A method for preparing compound D or a pharmaceutically acceptable salt thereof, , characterized in that, The method comprises the steps of reacting compound A with compound B in the presence of a condensation reagent to form compound C, and reacting compound C in the presence of a reducing agent to form compound D, wherein the condensation reagent is selected from one or more of DCC, EDCI, BOP, DMAP, HOBT and EEDQ, and the reducing agent is selected from borane dimethyl sulfide. .

2. The method according to claim 1, characterized in that: The condensation reagent is selected from EDCI / HOBT.

3. The method according to claim 1 or 2, characterized in that: The molar ratio of compound A to EDCI is 1:0.5-1:

5.

4. The method according to claim 1 or 2, characterized in that: The molar ratio of compound A to HOBT is 1:0.5-1:

5.

5. The method according to claim 1 or 2, characterized in that: The reaction of compound A and compound B to form compound C further comprises an acid binding agent, and the acid binding agent is selected from one or more of pyridine, triethylamine, diisopropylethylamine, and triethanolamine.

6. The method according to claim 1 or 2, characterized in that: Compound A reacts with compound B in the presence of EDCI, HOBT and triethylamine to form compound C, wherein the molar ratio of compound A to EDCI is 1:1-1:3, and the molar ratio of compound A to HOBT is 1:1-1:

3.

7. The method according to claim 1 or 2, characterized in that: The molar ratio of compound C to the reducing agent is 1:1~1:

2.

8. The method according to claim 1, characterized in that: The method comprises the following steps: a) Compound A reacts with Compound B in the presence of EDCI, HOBT and triethylamine to form Compound C; b) Compound C reacts in the presence of a reducing agent to form Compound D, wherein the reducing agent is selected from borane dimethyl sulfide, .

9. Compound C or a salt thereof, .

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