GLP1r agonist and preparation method for intermediate thereof
The process is simplified through the new preparation method, and the problems of raw material instability and high cost are solved, the stable production and high yield of compounds are achieved, and the use of precious metal catalysts is avoided.
Patent Information
- Application Number
- PCT/CN2024/102861
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-01-02
- Filing Date
- 2024-07-01
- Publication Date
- 2025-03-06
AI Technical Summary
In the prior art, the raw material 3-(4-(bromomethyl)-3-fluorophenyl)oxetane is unstable and highly sensitized, and the use of noble metal palladium catalysts leads to high costs.
By providing a new preparation method of 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidine-4-yl)pyridine (Formula XI), the process is simplified, the raw material cost is reduced, and the use of noble metal catalysts is avoided.
The stability and safety of the raw materials are achieved, the production costs are reduced, the yields of compound XI and target compound I are improved, and the use of precious metal catalysts is avoided.
Smart Images
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Figure PCTCN2024102861-FTAPPB-I100003
Abstract
Description
A preparation method of GLP1R agonist and its intermediate Technical Field
[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI) and (S)-2-((4-(6-((2-fluoro-4-(oxetane-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (Formula I), intermediates of a GLP-1 receptor agonist. Background Art
[0002] (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (compound of Formula I) is a non-peptide small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist with a molecular weight of 586.26 and a chemical structure as follows:
[0003] Invention patent WO 2022 / 268152 Al discloses for the first time a compound of formula I and a feasible preparation method thereof, using 3-(4-(bromomethyl)-3-fluorophenyl)oxetane and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate as raw materials, undergoing nucleophilic substitution and removal of the Boc protecting group to obtain the intermediate XI of the present invention (specific steps are as follows), which is then substituted and hydrolyzed to obtain the compound of formula I. Among them, 3-(4-(bromomethyl)-3-fluorophenyl)oxetane is obtained by bromination of a benzyl alcohol derivative, and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate is obtained by hydroxylation of a 6-chloropyridine derivative catalyzed by a palladium catalyst.
[0004] In kilogram-scale synthesis scale-up experiments, the raw material 3-(4-(bromomethyl)-3-fluorophenyl)oxetane used in the above-mentioned route is unstable and highly allergenic. Even with proper protection, the experimenters still experienced skin rashes or ulcers, posing a safety hazard in industrial production. Furthermore, the 6-hydroxyl group in tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate needs to be converted from a chloropyridine derivative in the presence of a precious metal palladium catalyst, which is costly. Therefore, it is highly necessary to seek a process route with stable raw materials, controllable costs, and ease of production.
[0005] Summary of the Invention
[0006] In order to overcome the problems of unstable and highly sensitized raw materials or excessively high costs described in the background art, the present invention provides a novel method for preparing 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI). This method overcomes the instability and safety hazards of 3-(4-(bromomethyl)-3-fluorophenyl)oxetane, effectively simplifies the steps, and reduces the cost of raw materials. The process is as follows:
[0007] Wherein, R is an amino protecting group, which is independently selected from one of benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc), p-methoxybenzyl (PMB), benzyl (Bn), trityl (Trt), p-toluenesulfonyl (Tos), phthaloyl (Pht), and allyloxycarbonyl (Alloc); wherein, R x is selected from Cl, Br and I, such as Cl.
[0008] The process provided by the present invention uses compound 1 and a 6-halopyridine derivative as raw materials, generates compound X-1 through an affinity substitution reaction, removes the amino protecting agent to obtain a compound of formula XI, and then obtains a compound of formula I through substitution, hydrolysis and other steps of the compound of formula XI. DETAILED DESCRIPTION
[0009] The present invention provides a novel method for preparing 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI), comprising the following steps:
[0010] a-1) Compound X is dissolved in an organic solvent, and compound 1 is added, and reacted in the presence of a base to obtain compound X-1:
[0011] a-2) using a suitable solvent and reaction conditions to remove the amino protecting agent R to obtain compound XI:
[0012] wherein said R is independently selected from benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl; said R x is selected from Cl, Br and I, such as Cl.
[0013] In some embodiments, the R is independently selected from benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl, preferably tert-butyloxycarbonyl.
[0014] In some embodiments, the organic solvent used in step a-1) is an aprotic solvent selected from dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, toluene, tetrahydrofuran, pyridine and 2-methyltetrahydrofuran; preferably dioxane and toluene.
[0015] In some embodiments, the base used in step a-1) is selected from sodium hydroxide, sodium bicarbonate, lithium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, n-butyllithium, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS), preferably potassium tert-butoxide and potassium hydroxide.
[0016] In some embodiments, the molar ratio of the base used in step a-1) to compound 1 is selected from 1:1 to 4:1, preferably 1:1 to 3:1.
[0017] In some embodiments, the molar ratio of compound X to compound 1 in step a-1) is 3:1 to 1:1.
[0018] In some embodiments, after adding Compound X and Compound 1 in step a-1), the temperature can be controlled to T1 and then lowered to room temperature.
[0019] In some embodiments, T1 in step a-1) is selected from 30 to 130°C, preferably 60 to 100°C, such as 80 to 100°C.
[0020] In some embodiments, the solvent used in step a-2) is selected from dichloromethane, methanol, tetrahydrofuran, ethyl acetate, chloroform, acetonitrile and DMF; preferably dichloromethane.
[0021] In some embodiments, the reaction temperature of step a-2) is selected from -20 to 50°C.
[0022] In some embodiments, after the reaction in step a-1) is completed, post-treatment may be optionally performed, and the post-treatment includes one or more of extraction, washing, drying, concentration, and filtration.
[0023] In some embodiments, after the reaction of step a-2) is completed, post-treatment may be optionally performed, and the post-treatment includes one or more of extraction, washing, drying, concentration, and filtration.
[0024] As a specific embodiment, step a-1) can be to dissolve compound X in an organic solvent, then add a base and stir to mix, then add compound 1, control the temperature at 25-130°C, react for 1-20 hours, cool to room temperature, add an extraction solvent and water to the reaction solution for extraction, separate the water layer, wash the organic layer with purified water or brine, dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate until there is no fraction, then pulp, and place the filter cake at 35-45°C under reduced pressure and dry for 10-12 hours to obtain the intermediate compound X-1.
[0025] As a specific embodiment, when R is tert-butyloxycarbonyl (Boc), a process route of the present invention is:
[0026] As a specific embodiment, when R is benzyl (Bn), a process route of the present invention is:
[0027] The beneficial effects of this technical solution are: compound 1 can be stably stored at room temperature and is non-sensitizing; and compound X (including compounds X2 and X3) has no hydroxyl substitution, avoiding the use of precious metal palladium catalysts, effectively reducing raw material costs, and achieving an increase in the yield of compound XI.
[0028] The present invention further provides a method for preparing a compound of formula I via compound XI, the process comprising the following steps:
[0029] a-3) Compound XI is dissolved in an organic solvent, and a base is added to react with compound V to obtain compound VI:
[0030] a-4) Compound XI is dissolved in an organic solvent, and a base is added to react to obtain compound I:
[0031] In some embodiments, the organic solvent used in step a-3) is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and n-hexane, preferably N,N-dimethylformamide.
[0032] In some embodiments, the molar ratio of formula XI to formula V in step a-3) is 1:1 to 2:1.
[0033] In some embodiments, the base used in step a-3) is selected from sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, n-butyllithium, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS); preferably potassium tert-butoxide, sodium bicarbonate, and potassium carbonate.
[0034] In some embodiments, the molar ratio of the base used in step a-3) to compound XI is selected from 1:1 to 3:1.
[0035] In some embodiments, the organic solvent used in step a-4) is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol, preferably methanol.
[0036] In some embodiments, the base used in step a-4) is selected from sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, n-butyllithium, lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS); preferably potassium tert-butoxide, sodium bicarbonate, and lithium hydroxide.
[0037] In some embodiments, the molar ratio of the base used in step a-4) to compound VI is selected from 1:1 to 5:1.
[0038] In some embodiments, after the reaction of step a-3) is completed, post-treatment may be optionally performed, and the post-treatment includes one or more of extraction, washing, drying, concentration and filtration.
[0039] In some embodiments, after the reaction of step a-4) is completed, post-treatment may be optionally performed, and the post-treatment includes one or more of extraction, washing, drying, concentration and filtration.
[0040] In a specific embodiment, step a-3) can be performed by dissolving compound XI in an organic solvent, stirring to obtain a clear solution, sequentially adding a base and compound V, and reacting at 20-100°C under a nitrogen atmosphere with stirring for 0.5-18 hours. The reaction solution is then poured dropwise into water, and the precipitated solid is collected. The solid is dissolved in an organic solvent, then washed with saline or purified water, and the organic layer is dried over anhydrous sodium sulfate. The filtrate is concentrated to a free fraction and then slurried with methyl tert-butyl ether. The filter cake is then dried under reduced pressure at 35-45°C for 1-12 hours to obtain compound VI.
[0041] In a specific embodiment, step a-4) can be: dissolving compound VI in an organic solvent, adding an aqueous solution of lithium hydroxide with stirring, reacting at 0-60°C under a nitrogen atmosphere for 0.5-24 hours, diluting the reaction solution with water, washing the aqueous phase with an organic solvent, separating the organic phase, adjusting the aqueous phase to acidity, adding an organic solvent for extraction, combining the organic phases, adding n-heptane to the organic phase, collecting the precipitated solid, and then slurrying with methyl tert-butyl ether. The filter cake is dried under reduced pressure at 35-45°C for 1-12 hours to obtain the target compound I.
[0042] The beneficial effects of this technical solution are:
[0043] 1. The present invention overcomes the hidden dangers of instability and high sensitization of the raw material 3-(4-(bromomethyl)-3-fluorophenyl)oxetane used in the prior art, avoids the use of precious metal palladium catalyst, significantly reduces costs, and thus obtains the process route described in this application with stable raw materials, controllable costs, and application to industrial scale-up.
[0044] 2. By optimizing the reaction solvent system and reaction conditions and using an appropriate base, the yields of compound VI (from 22.0% in the prior art to over 80%) and compound I (from 18.6% in the prior art to over 90%) were increased.
[0045] 3. This process route avoids the use of column chromatography. The intermediates and products can be obtained by recrystallization or beating to obtain the required product purity, among which the intermediate purity is greater than 98% and the product purity is greater than 99%. BRIEF DESCRIPTION OF THE DRAWINGS
[0046] Figure 1: Compound X2-1 1 H NMR spectrum.
[0047] Figure 2: 1H NMR spectrum of compound X3-1.
[0048] Figure 3: Compound XI 1 H NMR spectrum.
[0049] Figure 4: Compound VI 1 H NMR spectrum.
[0050] Figure 5: Compound I 1 H NMR spectrum.
[0051] Figure 6: HPLC spectrum of compound X2-1.
[0052] Figure 7: HPLC profile of compound XI.
[0053] Figure 8: HPLC spectrum of compound VI.
[0054] Figure 9: HPLC profile of compound 1.
[0055] Example
[0056] The experimental methods in the examples of the present invention for which specific conditions are not specified are generally conventional conditions or conditions recommended by the raw material or product manufacturers; reagents for which the sources are not specified are generally conventional reagents available through commercial channels or can be prepared from known reagents by conventional methods.
[0057] The present invention will be further described in detail below with reference to specific embodiments.
[0058] Example 1.1: Preparation of Compound X-1 (When R is Boc, i.e., Preparation of Compound X2-1)
[0059] Under nitrogen, 120 mL of 1,4-dioxane, 18 g of compound X2, 10 g of compound 1, and 9.3 g of potassium tert-butoxide were added to a reaction flask in sequence. The temperature was raised to 100°C and the reaction was stirred for 18 hours. After cooling to room temperature, the reaction solution was diluted with 150 mL of ethyl acetate, followed by 200 mL of purified water. The mixture was stirred for 25 minutes and allowed to stand for stratification. The organic phase was collected and the aqueous phase was back-extracted once with 150 mL of ethyl acetate. The combined organic phases were washed with purified water and saturated brine (2 × 200 mL each), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 50 mL of ethyl acetate, stirred for 1 hour, and the insoluble matter was filtered off. The filtrate was diluted with 100 mL of n-hexane. The organic phase was poured into a pre-packed silica gel column, and the eluate was collected. The eluate was collected and concentrated to dryness, and a mixed solvent of methyl tert-butyl ether and n-hexane (V / V=1:20) was added and heated until the solution became clear, then cooled to room temperature for crystallization, filtered, and the filter cake was rinsed with n-hexane and dried in vacuo to obtain compound X2-1 (a total of 15.0 g, a molar yield of 61%, and a purity greater than 98.5%). 1 The H NMR spectrum is shown in Figure 1 , and the HPLC spectrum of X2-1 is shown in Figure 6 .
[0060] 1 H NMR (500MHz, chloroform-d) δ7.59–7.39(m,2H),7.18–7.11(m,2H),6.72(d,J=7.2Hz,1H), 6.62(d,J=8.2Hz,1H),5.43(s,2H),5.07(dd,J=8.3,6.1Hz,2H),4.73(t,J=6.3Hz ,2H),4.21(ddd,J=15.0,8.3,6.6Hz,2H),2.85(d,J=13.5Hz,2H),2.74(ddd,J=11 .8,8.1,3.7Hz,1H),1.93–1.82(m,2H),1.73(qd,J=12.6,4.4Hz,2H),1.49(s,9H).
[0061] HRMS (ESI): calculated [M+H] + 443.2341, measured value is 443.2349.
[0062] Example 1.2: Preparation of Compound X-1 (When R is Boc, i.e., Preparation of Compound X2-1)
[0063] Under nitrogen, 120 mL of 1,4-dioxane, 18 g of compound X2, 10 g of compound 1, and 9.3 g of potassium tert-butoxide were added to a reaction flask in sequence. The temperature was raised to 65°C and stirred for 7 hours. After cooling to room temperature, the reaction solution was diluted with 150 mL of ethyl acetate, followed by 200 mL of purified water. The mixture was stirred for 25 minutes, and the layers were allowed to stand. The organic phase was collected and the aqueous phase was back-extracted once with 150 mL of ethyl acetate. The combined organic phases were washed with purified water and saturated brine (2 × 200 mL each), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 150 mL of a mixture of ethyl acetate and n-hexane (V / V = 1:2). The above organic phase was filtered through a suction funnel filled with silica gel (about 30 g), and the filter cake was rinsed with a mixed solvent of n-hexane and ethyl acetate (V / V=1:1). The filtrate and the rinsing liquid were combined and concentrated to dryness. Then, a mixed solvent of methyl tert-butyl ether and n-hexane (V / V=1:4) was added and heated until the solution was clear. The mixture was then cooled to room temperature for crystallization, filtered, and the filter cake was rinsed with n-hexane and dried in vacuo to obtain compound X2-1 (16.4 g, molar yield 67%, purity greater than 98.5%).
[0064] Example 2.1: Preparation of Compound XI (Preparation of Compound XI when R is Boc)
[0065] Under nitrogen protection, 100 mL of dichloromethane and 10 g of compound X2-1 were added to the reaction flask in sequence. After stirring and dissolving, 20 mL of trifluoroacetic acid was added dropwise at -10°C. The temperature of the reaction solution was controlled below -5°C during the addition process and the solution was added within 30 minutes. Then the reaction was carried out at -5°C for 6 hours. The reaction solution was slowly poured into 800 mL of saturated sodium bicarbonate aqueous solution, the water layer was separated, and the organic layer was retained. The organic phase was washed with 10% sodium chloride aqueous solution (3×100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The concentrated crude product was beaten with ethyl acetate at 80°C for 2 hours, then cooled to room temperature and filtered, the filter cake was rinsed with ethyl acetate, and vacuum dried to obtain compound XI (6.5 g, molar yield 84%, purity greater than 99%). Compound XI 1 The H NMR spectrum is shown in FIG3 , and the HPLC spectrum of compound XI is shown in FIG7 .
[0066] 1H NMR(500MHz,DMSO-d6)δ9.23(s,1H),7.68(dd,J=8.2,7.3Hz,1H),7.61(t,J=7.9H z,1H),7.33–7.23(m,2H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.2Hz,1H),5.39(s,2H ), 4.93 (dd, J = 8.3, 6.0 Hz, 2H), 4.61 ( dd, J = 6.7, 6.0 Hz, 2H), 4.28 ( dd, J = 15.0, 8. 4,6.8Hz,1H),3.34(dt,J=12.7,3.5Hz,2H),3.06–2.88(m,3H),2.06–1.96(m,4H).
[0067] HRMS (ESI): calculated [M+H] + 343.1817, measured value is 343.1828.
[0068] Example 2.2: Preparation of Compound XI (Preparation of Compound XI when R is Boc)
[0069] Under nitrogen protection, 90 mL of dichloromethane and 30 mL of trifluoroacetic acid were added to the reaction flask in sequence. After the temperature dropped to -10 ° C, 10 g of compound X2-1 was added to the reaction flask. The reaction temperature was controlled to be between -5 ° C and 0 ° C and stirred. The reaction progress was monitored by TLC. The reaction was stopped in about 45 minutes. The reaction solution was slowly poured into 800 mL of saturated sodium carbonate aqueous solution, stirred for 30 minutes, and the water layer was separated. The organic phase was washed with 20% ammonium chloride aqueous solution (4 × 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The concentrated crude product was beaten with ethyl acetate at 80 ° C for 2 hours, then cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate and dried in vacuo to obtain compound XI (6.5 g, molar yield 84%, purity greater than 99%).
[0070] Example 3.1: Preparation of Compound X3-1 (When R is Bn, Preparation of Compound X3-1):
[0071] Under nitrogen, 120 mL of 1,4-dioxane, 17.4 g of compound X3, 10 g of compound 1, and 9.3 g of potassium tert-butoxide were added to the reaction flask in sequence. The temperature was raised to 100°C and the reaction was stirred for 18 hours. After cooling to room temperature, the reaction solution was diluted with 150 mL of ethyl acetate, followed by 200 mL of purified water. The mixture was stirred for 25 minutes and allowed to stand for stratification. The organic phase was collected and the aqueous phase was back-extracted once with 150 mL of ethyl acetate. The combined organic phases were washed with purified water and saturated brine (2 × 200 mL each) and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 50 mL of ethyl acetate, stirred for 1 hour, and the insoluble matter was filtered off. The filtrate was diluted with 100 mL of n-hexane. The organic phase was poured into a pre-packed silica gel column, and the eluate was collected. The eluate was collected and concentrated to dryness, and a mixed solvent of methyl tert-butyl ether and n-hexane (V / V=1:20) was added and heated until the solution became clear, then cooled to room temperature for crystallization, filtered, and the filter cake was rinsed with n-hexane and dried in vacuo to obtain compound X3-1 (18.8 g, molar yield 78.9%). 1 The H NMR spectrum is shown in Figure 2.
[0072] 1 H NMR(500MHz,DMSO-d6)δ7.61(dd,J=8.2,7.3Hz,1H),7.53(t,J=7.8Hz,1H),7.36–7.27(m,5H ),7.27–7.20(m,2H),6.85(d,J=7.3Hz,1H),6.65(d,J=8.1Hz,1H),5.37(s,2H),4.92(dd,J=8 .4,5.9Hz,2H),4.60(t,J=6.3Hz,2H),4.26(ddd,J=15.1,8.3,6.7Hz,1H),3.48(s,2H),2.90 (dt,J=11.8,3.4Hz,2H),2.57(tt,J=10.1,5.0Hz,1H),2.09–1.95(m,2H),1.82–1.69(m,4H).
[0073] HRMS (ESI): calculated [M+H] + 433.2286, measured value is 433.2275.
[0074] Example 3.2: Preparation of compound X3-1 (when R is Bn, preparation of compound X3-1):
[0075] Under nitrogen, 120 mL of 1,4-dioxane, 17.4 g of compound X3, 10 g of compound 1, and 9.3 g of potassium tert-butoxide were added to a reaction flask in sequence. The temperature was raised to 65°C and stirred for 7 hours. After cooling to room temperature, the reaction solution was diluted with 150 mL of ethyl acetate, followed by 200 mL of purified water. The mixture was stirred for 25 minutes, allowed to stand, and the organic phase was collected. The aqueous phase was back-extracted once with 150 mL of ethyl acetate. The combined organic phases were washed with purified water and saturated brine (2 × 200 mL each), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was dissolved in 150 mL of a mixture of ethyl acetate and n-hexane (V / V = 1:2). The above organic phase was filtered through a suction funnel filled with silica gel (about 30 g), and the filter cake was rinsed with a mixed solvent of n-hexane and ethyl acetate (V / V=1:2). The filtrate and the rinsing liquid were combined and concentrated to dryness. Then, a mixed solvent of methyl tert-butyl ether and n-hexane (V / V=1:4) was added and heated until the solution was clear. Then, the temperature was lowered to room temperature for crystallization, filtered, the filter cake was rinsed with n-hexane, and vacuum dried to obtain compound X3-1.
[0076] Example 4: Preparation of Compound XI (Preparation of Compound XI when R is Bn)
[0077] 10 g of compound X3-1 was dissolved in 100 mL of anhydrous methanol, followed by the addition of 1 g of 10% Pd / C. Hydrogen was introduced (1 atm) and the reaction was stirred at 45°C for 12 h. The Pd / C was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness. The crude product was slurried with ethyl acetate at 80°C for 2 h, then cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate and dried under vacuum to yield compound XI (7.2 g, molar yield 91%, purity >99%).
[0078] 1 H NMR(500MHz,DMSO-d6)δ9.23(s,1H),7.68(dd,J=8.2,7.3Hz,1H),7.61(t,J=7.9H z,1H),7.33–7.23(m,2H),6.88(d,J=7.3Hz,1H),6.71(d,J=8.2Hz,1H),5.39(s,2H ), 4.93 (dd, J = 8.3, 6.0 Hz, 2H), 4.61 ( dd, J = 6.7, 6.0 Hz, 2H), 4.28 ( dd, J = 15.0, 8. 4,6.8Hz,1H),3.34(dt,J=12.7,3.5Hz,2H),3.06–2.88(m,3H),2.06–1.96(m,4H).
[0079] HRMS (ESI): calculated [M+H] +343.1817, measured value is 343.1828.
[0080] Example 5: Preparation of Compound I
[0081] Under nitrogen protection, 60 mL of DMF and 6.0 g of compound XI were added to the reaction flask and stirred to dissolve. Then, 3.5 g of K2CO3 and 4.5 g of compound V were added in sequence. After stirring at room temperature for 60 min, the temperature was raised to 50°C and the reaction was continued for 6 h. After the reaction solution was cooled to room temperature, 360 mL of purified water was added, stirred for 2 h and filtered. The filter cake was dissolved with 120 mL of ethyl acetate, and the organic phase was washed twice with 60 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The concentrated crude product was slurried with 60 mL of methyl tert-butyl ether at 50°C for 2 h, then cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate and vacuum dried to obtain 8.5 g of compound VI with a molar yield of 81% and a purity greater than 99%. Compound VI 1 The H NMR spectrum is shown in FIG4 , and the HPLC spectrum of compound VI is shown in FIG8 .
[0082] 1 H NMR (500MHz, chloroform-d) δ8.19(d,J=1.5Hz,1H),7.97(dd,J=8.5,1.6Hz,1H),7.75(d,J=8.4Hz,1H),7.49(ddd,J=9.5,6.4,1.8Hz,2H),7.19–7.0 8(m,2H),6.73(d,J=7.2Hz,1H),6.61(d,J=8.1Hz,1H),5.44(s,2H),5.24(dd,J=7.0,3.2Hz,1H),5.06(dd,J=8.3,6.0Hz,2H),4.78(d,J=6.2 Hz,1H),4.74–4.68(m,3H),4.62(ddd,J=8.3,7.5,6.0Hz,1H),4.42(dt,J=9.1,6.0Hz,1H),4.24–4.14(m,1H),3.94(s,3H),3.01(dd,J=25. 2,11.0Hz,2H),2.82–2.70(m,1H),2.64(dt,J=11.1,6.5Hz,1H),2.56–2.44(m,1H),2.43–2.21(m,1H),1.88(ddd,J=21.9,11.8,6.0Hz,4H).
[0083] HRMS (ESI): calculated [M+H] + 601.2821, measured 601.2828.
[0084] 8.0g of compound VI and 80mL of methanol were added to the reaction flask at room temperature. 1.12g of lithium hydroxide monohydrate was dissolved in 10mL of purified water and then added to the reaction flask. The mixture was stirred at room temperature for 1h. The reaction temperature was raised to 50°C and stirred for 18 hours. After the reaction solution cooled to room temperature, 100mL of purified water was added and the methanol was removed under reduced pressure. The aqueous phase was washed once with 40mL of 2-methyltetrahydrofuran. The aqueous phase was retained and 60mL of 2-methyltetrahydrofuran was added again. Acetic acid was added dropwise to adjust the pH of the system to 5.4-5.6. The liquid was separated and the organic phase was retained and washed with 50mL of purified water. After separation, n-heptane was added dropwise to the organic phase. The precipitated solid was collected and then hot-beated with methyl tert-butyl ether at 50°C for 4h, cooled to room temperature, stirred for 4h, filtered, and the filter cake was rinsed with methyl tert-butyl ether. The resulting solid was placed in a vacuum dryer at 45°C to obtain 7.1g of compound I with a molar yield of 91% and a purity greater than 99%. Compound I 1 The HNMR spectrum is shown in FIG5 , and the HPLC spectrum of compound I is shown in FIG9 .
[0085] 1H NMR(500MHz,DMSO-d6)δ12.81(s,1H),8.29(d,J=1.5Hz,1H),7.82(dd,J=8.4,1.6Hz,1H),7.69– 7.58(m,2H),7.53(t,J=7.8Hz,1H),7.28(dd,J=11.3,1.7Hz,1H),7.22(dd,J=7.9,1.7Hz,1H),6. 86(d,J=7.3Hz,1H),6.66(d,J=8.1Hz,1H),5.39(d,J=2.1Hz,2H),5.13(qd,J=7.1,2.8Hz,1H),4. 90(dd,J=8.4,6.0Hz,2H),4.82(dd,J=15.2,7.3Hz,1H),4.68(dd,J=15.2,2.8Hz,1H),4.59(t,J= 6.3Hz,2H),4.52–4.44(m,1H),4.39(dt,J=9.0,5.8Hz,1H),4.25(ddd,J=15.1,8.4,6.8Hz,1H),3 .97(d,J=13.5Hz,1H),3.79(d,J=13.5Hz,1H),3.01(dt,J=11.4,3.9Hz,1H),2.86(dt,J=11.4,4. 0Hz,1H),2.72(dtd,J=11.1,8.1,6.1Hz,1H),2.61(tt,J=11.6,4.2Hz,1H),2.46(ddt,J=11.1,8. 9,7.0Hz,1H),2.22(dtd,J=35.9,11.4,2.9Hz,2H),1.76(dddd,J=38.0,20.7,13.4,10.7Hz,4H).
[0086] HRMS (ESI): calculated [M+H] + 587.2664, measured value is 587.2668.
[0087] Example 6: Preparation of Compound X-1 (When R is Boc, Preparation of Compound X2-1)
[0088] Under nitrogen, 100 mL of dry toluene, 18 g of compound X2, 10 g of compound 1, and 5.1 g of powdered potassium hydroxide were added sequentially to a reaction flask equipped with a water separator. The temperature was raised to 120°C and stirred for 1 hour. After cooling to room temperature, the reaction solution was diluted with 150 mL of ethyl acetate, followed by 200 mL of purified water. The mixture was stirred for 25 minutes, allowed to stand for stratification, and the organic phase was collected. The aqueous phase was back-extracted once with 150 mL of ethyl acetate. The combined organic phases were washed with purified water and saturated brine (2 × 200 mL each), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness.
[0089] Post-processing
[0090] The concentrated crude product was dissolved in 50 mL of ethyl acetate, stirred for 1 h, and then filtered to remove insoluble matter. The filtrate was diluted with 100 mL of n-hexane. The organic phase was poured into a pre-packed silica gel column, and the eluate was collected. The eluate was collected and concentrated to dryness, and a mixed solvent of methyl tert-butyl ether and n-hexane (V / V = 1:20) was added and heated until the solution became clear. The mixture was then cooled to room temperature for crystallization, filtered, and the filter cake was rinsed with n-hexane and dried in vacuo to obtain compound X2-1 (13.5 g, molar yield 55%).
[0091] Another post-treatment method used in Example 6 is as follows: the concentrated crude product is dissolved in 150 mL of a mixed solvent of ethyl acetate and n-hexane (V / V = 1:2). The resulting organic phase is filtered through a suction funnel filled with silica gel (approximately 30 g), and the filter cake is rinsed with a mixed solvent of n-hexane and ethyl acetate (V / V = 1:2). The filtrate and the rinse are combined and concentrated to dryness. Then, a mixed solvent of methyl tert-butyl ether and n-hexane (V / V = 1:4) is added and heated until the solution is clear. The mixture is then cooled to room temperature for crystallization, filtered, and the filter cake is rinsed with n-hexane and dried under vacuum to obtain compound X2-1.
[0092] Example 7: Preparation of Compound I
[0093] Under nitrogen protection, 60mL DMF and 6.0g compound XI were added to the reaction flask and stirred to dissolve. Then 3.5g sodium bicarbonate and 4.5g compound V were added in sequence. After stirring at room temperature for 60min, the temperature was raised to 50°C and the reaction was continued for 6h. After the reaction solution was cooled to room temperature, purified water was added, stirred for 2h and filtered. The filter cake was dissolved in ethyl acetate, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The concentrated crude product was slurried with methyl tert-butyl ether at 50°C for 2h, then cooled to room temperature and filtered. The filter cake was rinsed with ethyl acetate and dried under vacuum to obtain compound VI with a molar yield of 85%.
[0094] Compound VI and methanol were added to a reaction flask at room temperature. Lithium hydroxide monohydrate was dissolved in purified water and added to the reaction flask. The mixture was stirred at room temperature for 1 hour. The reaction temperature was raised to 50°C and stirred for 18 hours. After the reaction solution cooled to room temperature, purified water was added and acetic acid was added dropwise to adjust the pH of the system to 5-6. The precipitated solid was collected and then slurried with methyl tert-butyl ether at 50°C for 4 hours. After cooling to room temperature, the mixture was stirred for 4 hours and filtered. The filter cake was rinsed with methyl tert-butyl ether. The resulting solid was dried under vacuum to obtain Compound I in a molar yield of 90%.
[0095] The above embodiments are only used to understand the method and core concept of the present invention, rather than to limit the scope of the present invention. For those skilled in the art, any possible changes or replacements without departing from the concept of the present invention are within the scope of protection of the present invention.
Claims
1. A method for preparing 2-(2-fluoro-4-(oxetane-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI), comprising the steps of: a-1) Compound X is dissolved in an organic solvent, and compound 1 is added, and reacted in the presence of a base to obtain compound X-1: a-2) using a suitable solvent and reaction conditions to remove the amino protecting agent R to obtain compound XI: in, The R is independently selected from benzyloxycarbonyl, tert-butyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, p-toluenesulfonyl, phthaloyl and allyloxycarbonyl; the R x Selected from Cl, Br and I, preferably Cl.
2. The method of claim 1, wherein: The organic solvent used in step a-1) is an aprotic solvent selected from dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, toluene, tetrahydrofuran, pyridine and 2-methyltetrahydrofuran, preferably dioxane and toluene; And / or, the base used in step a-1) is selected from sodium hydroxide, sodium bicarbonate, lithium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, n-butyl lithium, lithium diisopropylamide and lithium hexamethyldisilazide, preferably potassium tert-butoxide and potassium hydroxide.
3. The method of claim 1, wherein: The molar ratio of the base used in step a-1) to compound 1 is selected from 1:1 to 4:1, preferably 1:1 to 3:1; And / or, in the step a-1), the mass ratio of compound X to compound 1 is 3:1 to 1:1; And / or, in step a-1), after adding compound X and compound 1, the temperature may be controlled to T1 and then dropped to room temperature; And / or, the T1 is selected from 30 to 130°C, preferably 60 to 100°C.
4. The method of claim 1, wherein: The solvent used in step a-2) is selected from dichloromethane, methanol, tetrahydrofuran, ethyl acetate, chloroform, acetonitrile and DMF, preferably dichloromethane; And / or, the reaction temperature of step a-2) is selected from -20 to 50°C.
5. A method for preparing (S)-2-((4-(6-((2-fluoro-4-(oxetane-3-yl)methyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid (Formula I), comprising the steps of: a-3) Compound XI is dissolved in an organic solvent, and a base is added to compound V to react to obtain compound VI: a-4) Compound XI is dissolved in an organic solvent, and a base is added to react to obtain compound I:
6. The method of claim 5, wherein: The organic solvent used in step a-3) is selected from acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and n-hexane, preferably N,N-dimethylformamide; And / or, in step a-3), the molar ratio of formula XI to formula V is 1:1 to 2:1; And / or, the molar ratio of the base used in step a-3) to compound XI is selected from 1:1 to 3:
1.
7. The preparation method according to claim 5, wherein The organic solvent used in step a-4) is selected from one or more of methanol, ethanol, isopropanol, n-butanol and tert-butanol, preferably methanol; And / or, the molar ratio of the base used in step a-4) to compound VI is selected from 1:1 to 5:
1.
8. The method according to claim 1 and the method according to claim 5, wherein: After the completion of step a-1), step a-2), step a-3) or step a-4), post-reaction treatment can be carried out independently, and the post-treatment includes one or more of extraction, washing, drying, concentration and filtration.
9. A compound of formula I, prepared by the method of claim 5.
10. The compound of formula I according to claim 9, which has a purity greater than 99%.
11. A compound of formula XI, prepared by the method of claim 1.
12. The compound of formula XI according to claim 11, which has a purity greater than 98%.
13. The preparation method of 2-(2-fluoro-4-(oxetanes-3-yl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Formula XI) as claimed in claim 1, and the use of compound of formula I (S)-2-((4-(6-((2-fluoro-4-(oxetanes-3-yl)methyl)oxy)pyridine-2-yl)piperidin-1-yl)methyl)-1-(oxetanes-2-ylmethyl)-1H-benzimidazole-6-carboxylic acid.
14. Use of a compound of formula I prepared by the method of claim 5 and a compound I as claimed in claim 9 or 10, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a GLP-1 receptor-mediated disease or condition and related diseases or conditions, preferably the GLP-1 receptor-mediated disease and related diseases are selected from diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperinsulinemia, etc.; wherein the diabetes includes but is not limited to T1D and / or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes and gestational diabetes, etc.