A method for synthesizing Boc-Lys(Dde)-OH

Abstract

The present application relates to a kind of synthesis method of Boc-Lys (Dde)-OH. Mainly solve its technical problems such as low industrial yield, high three wastes. The synthesis method of the present application includes the following steps: Boc-Lys-OH is reacted in ethanol and DMAP, dde-OH under alkaline conditions, to generate compound 1 Boc-Lys (Dde)-OH. Boc-Lys (Dde)-OH is an important intermediate of weight loss peptide.

Description

Technical Field

[0001] This invention relates to a method for synthesizing Boc-Lys(Dde)-OH (CAS: 444795-66-8). Background Technology

[0002] In many countries around the world, obesity and diabetes are caused by unhealthy lifestyle habits. Since the 1990s, scientists have discovered Exendin-4 (a precursor to exenatide) from the venom of the Gila demon lizard, which was approved for marketing in 2005, becoming the first GLP-1 receptor agonist. Liraglutide (approved in 2010) allows for once-daily injection, but patient compliance remains limited. In 2010, semaglutide was first stably bound to the GLP-1 receptor in a laboratory at the University of Copenhagen. The core goal of Tirzepatide's development is to overcome the limitations of traditional GLP-1 receptor agonists and develop more efficient dual- or multi-target drugs. As a pharmaceutical intermediate, Boc-Lys(Dde)-OH is an important fragment used in the synthesis of semaglutide and irzepatide. The Journal of the American Chemical Society (2002, vol. 124, #26, pp. 7678-7680) reported the synthesis of the target compound using DIEA as a base, but did not provide specific experimental procedures and yields. Comparative experiments using DIEA, triethylamine, and N-methylmorpholine as bases showed low yields due to incomplete reaction of the starting materials. Improving the conversion rate of the starting materials would require consuming large amounts of organic bases, which is not economically or environmentally feasible. To date, no industrial-scale synthetic method for Boc-Lys(Dde)-OH has been publicly reported. Summary of the Invention

[0003] The main objective of this invention is to provide a method for synthesizing Boc-Lys(Dde)-OH. This primarily addresses the technical problems of low yield and high pollution associated with this compound.

[0004] The technical solution of this invention is: a method for synthesizing Boc-Lys(Dde)-OH, comprising the following steps: reacting Boc-Lys-OH with DMAP and dde-OH in ethanol to generate the target compound Boc-Lys(Dde)-OH. The synthetic route is as follows:

[0005] The reaction is carried out at 80-85°C overnight (12-16 hours), the amount of DMAP used is 0.15 equivalents, and the ethanol is anhydrous ethanol.

[0006] The beneficial effects of this invention are as follows: This invention is the first to report an industrial method for synthesizing Boc-Lys(Dde)-OH using DMAP instead of DIEA. Experiments have shown that 0.15 eq. of DMAP can achieve a better yield. This invention features a unique reaction pathway, inexpensive raw materials, mild reaction conditions, and minimal waste liquid production. This method can also be used to synthesize other compounds with similar structures. Detailed Implementation Example 1

[0007] Step 1-1: Boc-Lys-OH (50 g, 203 mmol) and anhydrous ethanol (300 mL), DMAP (3.72 g, 30.5 mmol), and dde-OH (40.7 g, 223 mmol) were added to a 250 mL single-necked flask. The mixture was reacted at 80–85 °C for 12–16 hours under argon protection. Ethanol was removed by vacuum evaporation, and water (100 mL) and ethyl acetate (300 mL) were added. The mixture was stirred for 5 min, separated, and the organic phase was washed with 5% hydrochloric acid (100 mL). The mixture was dried over anhydrous sodium sulfate and evaporated to dryness (below 40 °C). Methyl tert-methyl ether was stirred to crystallize, and the crystals were dried at 45 °C to give the target compound (77.3 g, 164 mmol, 92.7%). 1 H NMR (400 MHz, DMSO) δ 13.26 (s, 1H), 12.47 (s, 1H), 6.95 (t, J = 72.1 Hz, 1H), 3.85 (tt, J = 36.9, 18.4 Hz, 1H),3.42 (dd, J = 12.5, 6.7 Hz, 2H), 2.49 (s, 3H), 2.28 (s, 4H), 1.76 – 1.50 (m,4H), 1.39 (s, 11H), 0.96 (s, 6H).

[0008] Steps 1-2: Add Boc-Lys-OH (50 g, 203 mmol) and anhydrous ethanol (300 mL), triethylamine (30.8 g, 305 mmol), and dde-OH (40.7 g, 223 mmol) to a 250 mL single-necked flask. React under argon protection at 80–85 °C for 12–16 hours. Remove the ethanol under vacuum, add water (100 mL) and ethyl acetate (300 mL), stir for 5 min, separate the layers, wash the organic phase with 5% hydrochloric acid (100 mL), dry to anhydrous sodium sulfate, and evaporate to dryness (below 40 °C). Crystallize by stirring with methyl ether, and dry at 45 °C to obtain the target compound (62.5 g, 152 mmol, 75%).

[0009] Steps 1-3: Add Boc-Lys-OH (50 g, 203 mmol) and anhydrous ethanol (300 mL), N-methylmorpholine (30.8 g, 305 mmol), and dde-OH (40.7 g, 223 mmol) to a 250 mL single-necked flask. React under argon protection at 80–85 °C for 12–16 hours. Remove the ethanol under vacuum, add water (100 mL) and ethyl acetate (300 mL), stir for 5 min, separate the layers, wash the organic phase with 5% hydrochloric acid (100 mL), dry to anhydrous sodium sulfate, and evaporate to dryness (below 40 °C). Crystallize by stirring with methyl ether, and dry at 45 °C to obtain the target compound (67.2 g, 164 mmol, 80.6%).

[0010] Steps 1-4: Add Boc-Lys-OH (50 g, 203 mmol) and anhydrous ethanol (300 mL), DIEA (39.4 g, 305 mmol), and dde-OH (40.7 g, 223 mmol) to a 250 mL single-necked flask. React under argon protection at 80–85 °C for 12–16 hours. Remove the ethanol under vacuum, add water (100 mL) and ethyl acetate (300 mL), stir for 5 min, separate the liquids, wash the organic phase with 5% hydrochloric acid (100 mL), dry to anhydrous sodium sulfate, and evaporate to dryness (below 40 °C). Crystallize the methyl ether under stirring, and dry at 45 °C to obtain the target compound (65.8 g, 160 mmol, 78.8%).

Claims

1. A method for synthesizing Boc-Lys(Dde)-OH, characterized in that: Boc-Lys-OH reacts with DMAP and dde-OH in ethanol to generate the target compound Boc-Lys(Dde)-OH. The synthetic route is as follows: 。 2. The method for synthesizing Boc-Lys(Dde)-OH according to claim 1, characterized in that: React overnight at 80-85℃.

3. The method for synthesizing Boc-Lys(Dde)-OH according to claim 1, characterized in that: The DMAP dosage is 0.15 equivalents.

4. The method for synthesizing Boc-Lys(Dde)-OH according to claim 1, characterized in that: The ethanol is anhydrous ethanol.

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