Synthesis method of deuterated marked GLP-1 key intermediate

Abstract

The invention discloses a synthesis method of a deuterated labeled GLP-1 key intermediate, which comprises the following steps: carrying out drug synthesis by taking tetrahydro-2, 2-dimethyl-4H-pyran-4-ketone as a raw material, and introducing a specific group to finish the synthesis of the GLP-1 key intermediate 5-(2, 2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-methyl formate, thereby obtaining the deuterated labeled GLP-1 key intermediate. The synthesis method is simple and convenient, all synthesis conditions are mild and controllable, the yield of each step is relatively high, and the synthesis method is a synthesis process of the deuterated marked 5-(2, 2-dimethyl tetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-methyl formate serving as the GLP-1 key intermediate for the first time at home and abroad; according to the method, the reaction conditions are optimized, the tetrahydro-2, 2-dimethyl-4H-pyran-4-ketone with lower price is used as a starting raw material, the material cost is saved, the total purity of the product reaches 99.9%, and the requirements of pharmacopeia can be completely met; the product yield and the deuteration ratio are high, generated impurities are few, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and specifically relates to a method for synthesizing a deuterated labeled GLP-1 key intermediate. Background Art

[0002] Diabetes is a chronic comprehensive disease characterized by glucose metabolism disorder caused by absolute or relative insulin deficiency or reduced insulin sensitivity of target cells. It is divided into type 2 diabetes and type 2 diabetes. Type 2 diabetes is an endocrine disease characterized by chronic hyperglycemia due to insulin resistance and / or insulin secretion defects. Type 2 diabetes accounts for more than 90% of diabetic patients.

[0003] At present, the following types of drugs can be used to treat type II diabetes: insulin secretagogues, metformin, α-glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, insulin and its analogs, etc., among which insulin and GLP-1 receptor agonists are one of the most effective diabetes treatment drugs. Insulin preparations are still the most widely used diabetes medications in the world, and about 30-40% of type II diabetes patients eventually need to use insulin. GLP-1 preparations mainly include exenatide, liraglutide, semaglutide, etc., which are suitable for type II diabetes patients whose blood sugar cannot be fully controlled by the combined use of metformin, sulfonylureas, etc. However, at present, insulin preparations and GLP-1 preparations are basically polypeptide drugs and injection preparations, and even oral semaglutide still has many restrictions on medication. Therefore, it is still necessary to further develop small molecule agonist drugs for GLP-1 receptors.

[0004] As a drug with great potential, GLP-1 receptor agonists are currently mostly administered by injection on the market. Oral small molecule GLP-1 receptor agonists can improve patient compliance and are the development trend of GLP-1 receptor agonists in the future. The research and development of small molecule GLP-1 receptor agonists can be found in: WO2009111700A2, WO2010114824A1, W02017078352A1, KR1020180101671A, WO2018056453A1 and W02018109607A1.

[0005] Chinese invention patent (CN116390926) discloses a method of using 5-bromoindole-2-carboxylic acid ethyl ester as the starting material, and obtaining 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)1H-indole-2-carboxylic acid ethyl ester after two steps of reaction and refining and purification with a total yield of 40-50%. This reaction cannot complete the positional deuteration, and the reaction process is as follows:

[0006]

[0007] The Chinese invention patent (CN109790161) discloses a method of using 5-bromoindole-2-carboxylic acid ethyl ester as the starting material, and obtaining 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)1H-indole-2-carboxylic acid ethyl ester after one step of reaction and refining and purification with a total yield of 70-80%. 2,2-dimethyltetrahydro-2H-pyran-4-ylzinc iodide is generated in situ, and then a coupling reaction is carried out, but accurate deuteration positioning cannot be performed. The reaction process is as follows:

[0008]

[0009] Compared with drug molecules before modification with deuterium atoms, deuterated drugs have the following advantages: 1) prolonging the half-life and / or blood concentration of drugs; 2) reducing the dosage or frequency of drug administration to achieve the same drug exposure, thereby improving patient compliance; 3) possibly blocking certain metabolic sites, reducing the production of toxic metabolites, and reducing drug toxicity; 4) preventing certain drugs from isomerizing in the body and losing their drug activity or even becoming toxic.

[0010] Since no research has been done on the deuterium labeling reaction of 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)1H-indole-2-carboxylic acid methyl ester, it is urgent to develop a synthetic method that can complete the deuterium labeling. Summary of the invention

[0011] In view of the above problems, the purpose of the present invention is to provide a method for preparing a deuterated GLP-1 key intermediate, which is simple to operate, has a high product yield and high purity, and is suitable for industrial production.

[0012] In order to achieve the above object, the technical solution adopted by the present invention is:

[0013] A method for synthesizing a deuterated GLP-1 key intermediate comprises the following steps:

[0014] Step 1: Synthesis of β-ketoester: dissolve tetrahydro-2,2-dimethyl-4H-pyran-4-one in dimethyl carbonate, and add a base in batches to react to obtain compound II tetrahydro-6,6-dimethyl-4-oxo-2H-pyran-3-carboxylic acid methyl ester;

[0015]

[0016] Step 2: Synthesis of methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate: dissolve compound II in a solvent, slowly add a base at low temperature, and then add a trifluoromethanesulfonyl reagent to obtain the product compound III;

[0017]

[0018] Step 3: Suzuki coupling: the catalyst and compound III are dissolved in a solvent under a nitrogen atmosphere, a base is added and the reaction is carried out at 40°C-100°C for 1 hour, 4-nitrophenylboronic acid pinacol ester is dissolved in the solution and added to the reaction solution, and the reaction is carried out at the same temperature for 4-8 hours to obtain compound IV 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid methyl ester;

[0019]

[0020] Step 4: hydrolysis reaction, dissolving compound IV in a solvent, adding a base, and reacting at 50° C.-100° C. for 0.5 h-5 h to obtain compound V 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid;

[0022]

[0023] Step 5: Hydrogenation reduction: Compound V is dissolved in a solvent, a catalyst is added, the mixture is reacted under a hydrogen atmosphere, and the mixture is filtered and concentrated to obtain a crude compound VI 4-(4-aminophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid;

[0024]

[0025] Step 6: Boc anhydride protection: Compound VI is dissolved in a solvent, di-tert-butyl dicarbonate is added, and the mixture is reacted at 0°C-50°C for 2-8 hours. The reaction solution is concentrated to obtain a crude compound VII 4-(4-((tert-butoxycarbonyl)amino)phenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid;

[0026]

[0027] Step 7: Decarboxylation and deuteration: Dissolve reactant VII, ligand 1, ligand 2, catalyst, and base in a solvent under a nitrogen atmosphere, react under light for 10-24 hours, and filter and concentrate to obtain the deuterated product compound VIII 4-

[0028] tert-Butyl (2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)carbamate;

[0029]

[0030] Step 8: Removal of Boc protecting group: Compound VIII is dissolved in a solvent, HCl solution is added, and the reaction mixture is reacted for 2-4 hours. The reaction solution is concentrated to obtain a crude product 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino;

[0031] Construction of indole reaction: 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino, methyl pyruvate, catalyst, activator, and 4M molecular sieves are dissolved in a solvent under an oxygen atmosphere, and reacted at 50°C-90°C for 12-20h to obtain the product compound IX 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester;

[0032]

[0033] Further, the base used in the reaction of step 1 is any one of potassium tert-butoxide, n-butyl lithium, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and sodium hydride, preferably potassium tert-butoxide; in the reaction of step 1, the ratio of tetrahydro-2,2-dimethyl-4H-pyran-4-one to dimethyl carbonate is 1:8-11.5 in molar terms; the ratio of tetrahydro-2,2-dimethyl-4H-pyran-4-one to potassium tert-butoxide is 1:1-1.6.

[0034] Furthermore, in the reaction of step 2, the trifluoromethanesulfonyl reagent used is any one of trifluoromethanesulfonic anhydride, tert-butyldimethylsilyl trifluoromethanesulfonate, and N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl imide), preferably N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl imide); the reaction temperature is controlled at -75°C-0°C; in the reaction of step 2, the base used is any one of sodium hydride, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and n-butyl lithium, preferably potassium bis(trimethylsilyl)amide; the solvent used is any one of tetrahydrofuran, ether, dichloromethane, and toluene, preferably tetrahydrofuran.

[0035] Furthermore, in the reaction of step 3, the solution used is any one of toluene / water, ethanol / benzene, ethanol / toluene, and water / benzene, preferably toluene / water, and the reaction temperature is controlled at 45°C-80°C; the base used is any one of cesium fluoride, cesium carbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate; the catalyst used is any one of palladium acetate, palladium chloride, and tetrakistriphenylphosphine palladium, preferably palladium acetate.

[0036] Furthermore, in the reaction of step 4, the base used is any one of sodium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide, and the reaction temperature is controlled to be 30-100°C; the solvent used is any one of methanol / water, 1.4-dioxane / water, and tetrahydrofuran, preferably methanol / water / 1.4-dioxane.

[0037] Furthermore, in the reaction of step 5, the catalyst used is any one of Pd / C, Pt / C, Ru / C, preferably Pd / C; the reaction pressure is 0Mpa-3Mpa, the reaction temperature is 25°C-80°C, preferably 2Mpa, 50°C; the solvent used is any one of methanol, ethanol, ethyl acetate, preferably methanol.

[0038] Furthermore, in the reaction of step 6, the solvent used is any one of methanol, ethanol, tetrahydrofuran, and dichloromethane, preferably ethanol; in the reaction of step 6, the molar ratio of compound VI to di-tert-butyl dicarbonate is 1:1.1-1.8.

[0039] Further, in the reaction of step 7, the base used is any one of cesium fluoride, cesium carbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate; the catalyst used is any one of ferric nitrate nonahydrate, ferrous acetate, ferric sulfate, and ferric acetylacetonate, preferably ferric nitrate nonahydrate; the ligand 1 used is any one of dimethylpyridinamine, 2,2'-bipyridine, 4,4'-bipyridine, and 6,6-dimethyl-2,2-bipyridine, preferably dimethylpyridinamine; the ligand 2 used is any one of bis(2,4,6-triisopropylphenyl) disulfide, p-toluene disulfide, and diphenyl disulfide, preferably bis(2,4,6-triisopropylphenyl) disulfide; the solvent used is any one of dichloroethane / heavy water, dichloromethane / heavy water, and tetrahydrofuran / heavy water, preferably dichloroethane / heavy water.

[0040] Further, in the reaction of step 8, the solvent used for deprotection is any one of methanol-HCl solution and 1.4-dioxane-HCl solution, preferably methanol-HCl solution; the catalyst used is any one of palladium acetate, palladium dichloride, bis(triphenylphosphine)palladium chloride, tris(dibenzylideneacetone)dipalladium, preferably palladium acetate; the activator used is any one of acetic acid, pivalic acid, and trifluoromethanesulfonic acid, preferably acetic acid; the solvent used is any one of acetonitrile, toluene, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylacetamide.

[0041] The technical solution of the present invention has the following beneficial effects:

[0042] 1. The present invention uses tetrahydro-2,2-dimethyl-4H-pyran-4-one as a raw material to start drug synthesis, and completes the synthesis of the deuterated product 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester, a key intermediate of GLP-1, by introducing a specific group;

[0043] 2. All synthetic conditions are mild and controllable, and the yield of each step is high. This is the first synthetic process for deuterium-labeled 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester, a key intermediate of GLP-1, in China and abroad;

[0044] 3. The reaction conditions were optimized, and the low-priced tetrahydro-2,2-dimethyl-4H-pyran-4-one was used as the starting material, saving material costs;

[0045] 4. The 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester produced by the method of the present invention has the appearance of a white solid and a purity of 99.6%. The single impurity control is less than 0.10%, and the total purity of the product reaches 99.9%, which can fully meet the requirements of the pharmacopoeia. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1.1 to Figure 1.8 is the hydrogen spectrum of the product of the present invention;

[0047] Figure 2.1-Figure 2.5 is the carbon spectrum of the product of the present invention;

[0048] Figure 3.1 is the fluorine spectrum of the product of the present invention; DETAILED DESCRIPTION

[0049] To make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation methods obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0050] Example 1

[0051] (1) Synthesis of β-ketoesters

[0052] Under nitrogen atmosphere, tetrahydro-2,2-dimethyl-4H-pyran-4-one (2g, 15.6mmol) was dissolved in 15ml of dimethyl carbonate, the temperature of the reaction solution was controlled at -10°C, and potassium tert-butoxide (2g, 18mmol) was added in batches. The reaction was carried out at -10°C for 2h, and then returned to room temperature. The reaction gave tetrahydro-6,6-dimethyl-4-oxo-2H-pyran-3-carboxylic acid methyl ester with a yield of 88.4% and the product was a light yellow oil. 1 H NMR (400MHz, CDCl3) δ11.72 (s, 1H), 4.25 (d, J = 1.8Hz, 2H), 3.74 (d, J = 2.2Hz, 3H), 2.20 (t, J = 1.8Hz, 2H), 1.24 (s, 6H). The hydrogen spectrum of the product is shown in the attached Figure 1.1 shown.

[0053] (2) Synthesis of methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate. Under nitrogen atmosphere, tetrahydro-6,6-dimethyl-4-oxo-2H-pyran-3-carboxylate (1.58 g, 10 mmol) was dissolved in 25 ml of ultra-dry tetrahydrofuran. The reaction solution was cooled to -78°C and 12 ml of potassium bis(trimethylsilyl)amide (1 M) was added dropwise. The mixture was returned to room temperature for activation for 2-3 h. The reaction solution was cooled to -78°C again. N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonylimide) (4.71 g, 12 mmol) was dissolved in 20 ml of tetrahydrofuran and added dropwise to the reaction solution. The mixture was returned to room temperature and reacted for 8 h. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous MgSO4, rotary evaporated and collected. A colorless oily product, methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate, was obtained in a yield of 95.4%.

[0054] 1 H NMR (400MHz, CDCl3) δ4.41 (s, J = 2.4 Hz, 2H), 3.77 (s, J = 1.8 Hz, 3H), 2.32 (s, J = 2.4 Hz, 2H), 1.25 (s J = 2.0 Hz, 6H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.2 shown.

[0055] 19 F NMR (377MHz, CDCl3) δ-74.89. The fluorine spectrum of the product is as attached Figure 3.1 shown.

[0056] (3) Suzuki coupling. Add palladium acetate (18.63 mg, 83 μmol), triphenylphosphine (197 mg, 0.75 mmol), 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylic acid methyl ester (3.18 g, 10 mmol) into a Shrek bottle. Replace nitrogen three times, add 30 ml of toluene and 30 ml of water, and then add N,N-diisopropylethylamine (2.07 g, 16 mmol). Heat to 70°C and react for 1 h. Dissolve 4-nitroboronic acid pinacol (3.18 g, 10 mmol) in 30 ml of toluene and add to the reaction solution. React at 70°C for 6 h. The mixture was filtered, extracted with ethyl acetate, dried, and rotary evaporated to obtain methyl 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylate as a white solid in a yield of 94.6%.

[0057] 1 H NMR (400MHz, CDCl3) δ8.22-8.17 (d, 2H), 7.30-7.23 (d, 2H), 4.47 (s, J = 2.4Hz, 2H), 3.52 (s, J = 1.2Hz, 3H), 2.32 (s, J = 3.1Hz, 2H), 1.31 (s, J = 1.2Hz, 6H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.3 shown.

[0058] (4) Hydrolysis reaction: 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid methyl ester (1 g, 3.8 mmol) was added to 15 ml of methanol, 15 ml of 1.4-dioxane, and 15 ml of 1M NaOH aqueous solution, and reacted at 100° C. for 1 h. The pH was adjusted to <6 with 1M HCl, extracted with ethyl acetate, dried, and rotary evaporated to obtain a yellow solid 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid with a yield of 98.2%. The product was directly processed into the next step without purification.

[0059] (5) Hydrogenation reduction: 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid (2 g) was dissolved in 15 ml of methanol and 3 ml of ethyl acetate, Pd / C (200 mg) was added, and the mixture was reacted at 2 MPaH2 and 50°C for 24 h. The mixture was filtered and concentrated to give a crude product of a yellow solid (4-aminophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid in a yield of 97.2%.

[0060] (6) Boc anhydride protection. (4-Aminophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid (1.99 g, 8 mmol) was dissolved in 30 ml of ethanol, di-tert-butyl dicarbonate (1.92 g, 8.8 mmol) was added, and the mixture was reacted at room temperature for 6 h. The reaction solution was concentrated to obtain a crude product 4-(4-((tert-butoxycarbonyl)amino)phenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid, which was recrystallized to obtain a white product with a yield of 95%.

[0061] 1 H NMR (400MHz, DMSO-d6) δ11.78 (s, 1H), 9.22 (s, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 4.01-3.82 (m, 2H), 3.16 (m, J = 13.5, 4.1 Hz, 1H), 2.76 (s, J = 3.9 Hz, 1H), 2.44 (t, J = 13.1 Hz, 1H), 1.47 (s, 9H), 1.24 (s, 3H), 1.21 (s, 3H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.4 shown.

[0062] 13 C NMR (101MHz, DMSO-d6)δ173.54,153.28,137.78,137.53,127.78,118.24,79.26,72.25,63.56,45.44,36.13,36.09,31.91,28.62,22.14. The carbon spectrum of the product is shown in the attached Figure 2.1 shown.

[0063] (7) Decarboxylation and hydrogenation: 4-(4-((tert-Butyloxycarbonyl)amino)phenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid (1.25 g, 5 mmol), bis(2,4,6-triisopropylphenyl) disulfide (59 mg, 0.125 mmol), dimethylpyridinium amine (50 mg, 0.25 mmol), ferric nitrate nonahydrate (50.5 mg, 0.125 mmol), and sodium carbonate (53 mg, 0.5 mmmol) were dissolved in 5 mmol of dichloroethane and 5 mmol of water under nitrogen atmosphere, and the mixture was reacted under light for 18 h. The mixture was filtered and concentrated to obtain tert-butyl 4-(2,2-dimethyltetrahydro-2H-pyran)phenyl)carbamate, which was purified by column chromatography to obtain a pure product as a white powder with a yield of 80%.

[0064] 1H NMR (400MHz, Chloroform-d) δ7.29 (d, J = 8.2 Hz, 2H), 7.16-7.10 (d, 2H), 6.45 (s, 1H), 3.87-3.74 (m, 2H), 2.88 (tt, J = 12.2, 4.2 Hz, 1H), 1.72-1.63 (m, 3H), 1.56 (d, J = 12.8 Hz, 1H), 1.51 (s, 9H), 1.30 (s, 3H), 1.26 (s, 3H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.5 shown.

[0065] 13 C NMR (101MHz, Chloroform-d)δ152.98,140.70,136.58,127.22,118.88,71.92,61.74,44.38,36.87,33.55,31.76,28.38,21.80. The carbon spectrum of the product is shown in the attached Figure 2.2 shown.

[0066] Decarboxylation and deuteration: 4-(4-((tert-Butyloxycarbonyl)amino)phenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid (1.25 g, 5 mmol), bis(2,4,6-triisopropylphenyl) disulfide (59 mg, 0.125 mmol), dimethylpyridinium amine (50 mg, 0.25 mmol), ferric nitrate nonahydrate (50.5 mg, 0.125 mmol), and sodium carbonate (53 mg, 0.5 mmmol) were dissolved in 5 mmol of dichloroethane and 5 mmol of heavy water under nitrogen atmosphere, and reacted under light for 18 h. The deuterated product 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)carbamic acid tert-butyl ester was obtained by column chromatography purification to obtain a pure product as a white powder with a yield of 75% and a deuteration ratio of 95%. 1 H NMR (400MHz, Chloroform-d) δ7.31 (d, J = 8.2 Hz, 2H), 7.18-7.13 (d, 2H), 6.49 (s, 1H), 3.89-3.76 (m, 2H), 2.89 (ddt, J = 12.5, 8.9, 4.0 Hz, 1H), 1.69 (dd, J = 13.0, 4.0 Hz, 2H), 1.32 (s, 3H), 1.28 (s, 3H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.6 shown.

[0067] 13C NMR (101MHz,CDCl3)δ152.90,140.79,136.48,127.25,118.86,80.44,71.90,61.70,44.38,36.79,33.0-33.4(m),31.76,28.36,21.78. The carbon spectrum of the product is shown in the attached Figure 2.3 shown.

[0068] HRMS(ESI)m / z calcd for C 18 H 26 DNO3Na + (M+Na) + =329.1946, found329.1926.

[0069] (8) Removal of Boc protecting group: tert-butyl 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)carbamate (1.53 g, 5 mmol) was dissolved in 30 ml of saturated HCl-methanol solution and reacted for 4 h. The reaction solution was concentrated to obtain a crude product of 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino.

[0070] Construction of indole reaction: 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino (1.03 g, 5 mmol), methyl pyruvate (1.02 g, 10 mmol), palladium acetate (112.25 mg, 0.5 mmol), acetic acid (1.2 g, 20 mmol), and 4M molecular sieves (200 mg) were dissolved in dimethyl sulfoxide under an oxygen atmosphere, and reacted at 80°C for 18 h to obtain the product 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester, which was purified by column chromatography to obtain a white solid with a two-step yield of 90%.

[0071] 1 H NMR (400 MHz, Chloroform-d) δ8.88 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.6, 1.7 Hz, 1H), 7.20 (dd, J = 2.2, 1.0 Hz, 1H), 3.96 (s, 3H), 3.90-3.80 (m, 2H), 3.09-2.99 (m, 1H), 1.78 (dd, J = 13.0, 3.8 Hz, 3H), 1.36 (s, J = 3.0 Hz, 3H), 1.31 (s, 3H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.7 shown.

[0072] 13C NMR (101MHz,CDCl3)δ162.42,138.71,135.68,127.71,127.37,125.30,119.78,111.86,108.62,72.02,61.86,52.02,44.84,37.45,33.36-33.38(m),31.79,21.84. The carbon spectrum of the product is shown in the attached Figure 2.4 shown.

[0073] HRMS(ESI)m / z calcd for C 17 H 20 DNO3Na + (M+Na) + =311.1476, found 311.1488. 5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid methyl ester.

[0074] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.6, 1.7 Hz, 1H), 7.18 (dd, J = 2.1, 1.0 Hz, 1H), 3.95 (s, 3H), 3.88-3.81 (m, 2H), 3.02 (tt, J = 12.4, 4.2 Hz, 1H), 1.81-1.73 (m, 4H), 1.34 (s, 3H), 1.29 (s, 3H). The hydrogen spectrum of the product is shown in the attached figure. Figure 1.8 shown.

[0075] 13 C NMR (101MHz, CDCl3)δ162.47,138.68,135.74,127.71,127.37,125.29,119.77,111.89,108.62,72.03,61.90,52.02,44.84,37.54,33.93,31.80,21.84. The carbon spectrum of the product is shown in the attached Figure 2.5 shown.

[0076] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for synthesizing a deuterated GLP-1 key intermediate, It is characterized in that The steps include: Step 1: Synthesis of β-ketoester: dissolve tetrahydro-2,2-dimethyl-4H-pyran-4-one in dimethyl carbonate, and add a base in batches to react to obtain compound II tetrahydro-6,6-dimethyl-4-oxo-2H-pyran-3-carboxylic acid methyl ester; Step 2: Synthesis of methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydro-2H-pyran-3-carboxylate: dissolve compound II in a solvent, slowly add a base at low temperature, and then add a trifluoromethanesulfonyl reagent to obtain the product compound III; Step 3: Suzuki coupling: the catalyst and compound III are dissolved in a solvent under a nitrogen atmosphere, a base is added and the reaction is carried out at 40°C-100°C for 1 hour, 4-nitrophenylboronic acid pinacol ester is dissolved in the solution and added to the reaction solution, and the reaction is carried out at the same temperature for 4-8 hours to obtain compound IV 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid methyl ester; Step 4: hydrolysis reaction, dissolving compound IV in a solvent, adding a base, and reacting at 50° C.-100° C. for 0.5 h-5 h to obtain compound V 6,6-dimethyl-4-(4-nitrophenyl)-5,6-dihydro-2H-pyran-3-carboxylic acid; Step 5: Hydrogenation reduction: Compound V is dissolved in a solvent, a catalyst is added, the mixture is reacted under a hydrogen atmosphere, and the mixture is filtered and concentrated to obtain a crude compound VI 4-(4-aminophenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid; Step 6: Boc anhydride protection: Compound VI is dissolved in a solvent, di-tert-butyl dicarbonate is added, and the mixture is reacted at 0°C-50°C for 2-8 hours. The reaction solution is concentrated to obtain a crude compound VII 4-(4-((tert-butoxycarbonyl)amino)phenyl)-6,6-dimethyltetrahydro-2H-pyran-3-carboxylic acid; Step 7: Decarboxylation and deuteration: reactant VII, ligand 1, ligand 2, catalyst and base are dissolved in a solvent under a nitrogen atmosphere, reacted under light for 10-24 hours, filtered and concentrated to obtain the deuterated product compound VIII tert-butyl 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)carbamate; Step 8: Removal of Boc protecting group: Compound VIII is dissolved in a solvent, HCl solution is added, and the reaction mixture is reacted for 2-4 hours. The reaction solution is concentrated to obtain a crude product 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino; Construction of indole reaction: 4-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)phenyl)amino, methyl pyruvate, catalyst, activator, and 4M molecular sieves are dissolved in a solvent under an oxygen atmosphere, and reacted at 50°C-90°C for 12-20h to obtain the product compound IX 5-(2,2-dimethyltetrahydro-2H-pyran-4-yl-5-d)-1H-indole-2-carboxylic acid methyl ester; 2. A method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that The base used in the reaction of step 1 is any one of potassium tert-butoxide, n-butyl lithium, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, and sodium hydride, preferably potassium tert-butoxide; in the reaction of step 1, the molar ratio of tetrahydro-2,2-dimethyl-4H-pyran-4-one to dimethyl carbonate is 1:8-11.5; the molar ratio of tetrahydro-2,2-dimethyl-4H-pyran-4-one to potassium tert-butoxide is 1:1-1.

6.

3. A method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 2, the trifluoromethanesulfonyl reagent used is any one of trifluoromethanesulfonic anhydride, tert-butyldimethylsilyl trifluoromethanesulfonate, and N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl imide), preferably N-(5-chloro-2-pyridyl)bis(trifluoromethanesulfonyl imide); the reaction temperature is controlled at -75°C to 0°C; in the reaction of step 2, the base used is any one of sodium hydride, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and n-butyllithium, preferably potassium bis(trimethylsilyl)amide; the solvent used is any one of tetrahydrofuran, ether, dichloromethane, and toluene, preferably tetrahydrofuran.

4. A method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 3, the solution used is any one of toluene / water, ethanol / benzene, ethanol / toluene, and water / benzene, preferably toluene / water, and the reaction temperature is controlled at 45°C-80°C; the base used is any one of cesium fluoride, cesium carbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate; the catalyst used is any one of palladium acetate, palladium chloride, and tetrakistriphenylphosphine palladium, preferably palladium acetate.

5. The method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 4, the base used is any one of sodium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate, preferably sodium hydroxide, and the reaction temperature is controlled to be 30-100° C.; the solvent used is any one of methanol / water, 1.4-dioxane / water, and tetrahydrofuran, preferably methanol / water / 1.4-dioxane.

6. The method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 5, the catalyst used is any one of Pd / C, Pt / C, Ru / C, preferably Pd / C; the reaction pressure is 0Mpa-3Mpa, the reaction temperature is 25°C-80°C, preferably 2Mpa, 50°C; the solvent used is any one of methanol, ethanol, ethyl acetate, preferably methanol.

7. The method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 6, the solvent used is any one of methanol, ethanol, tetrahydrofuran, and dichloromethane, preferably ethanol; in the reaction of step 6, the molar ratio of compound VI to di-tert-butyl dicarbonate is 1:1.1-1.

8.

8. The method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 7, the base used is any one of cesium fluoride, cesium carbonate, sodium carbonate, and potassium carbonate, preferably sodium carbonate; the catalyst used is any one of ferric nitrate nonahydrate, ferrous acetate, ferric sulfate, and ferric acetylacetonate, preferably ferric nitrate nonahydrate; the ligand 1 used is any one of dimethylpyridinamine, 2,2'-bipyridine, 4,4'-bipyridine, and 6,6-dimethyl-2,2-bipyridine, preferably dimethylpyridinamine; the ligand 2 used is any one of bis(2,4,6-triisopropylphenyl) disulfide, p-toluene disulfide, and diphenyl disulfide, preferably bis(2,4,6-triisopropylphenyl) disulfide; the solvent used is any one of dichloroethane / heavy water, dichloromethane / heavy water, and tetrahydrofuran / heavy water, preferably dichloroethane / heavy water.

9. The method for synthesizing a deuterated GLP-1 key intermediate according to claim 1, It is characterized in that In the reaction of step 8, the solvent used for deprotection is any one of methanol-HCl solution and 1.4-dioxane-HCl solution, preferably methanol-HCl solution; the catalyst used is any one of palladium acetate, palladium dichloride, bis(triphenylphosphine)palladium chloride, tris(dibenzylideneacetone)dipalladium, preferably palladium acetate; the activator used is any one of acetic acid, pivalic acid, and trifluoromethanesulfonic acid, preferably acetic acid; the solvent used is any one of acetonitrile, toluene, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylacetamide.

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