Selective reduction method of ketal (acetal) for preparing tamiflu epoxy intermediate

Abstract

The invention discloses a selective reduction method of 5-O-methylsulfonyl ethyl shikimic acid ketal (acetal), which can be used for preparing a Tamiflu key intermediate (Roch epoxy intermediate). A series of ketal (acetal) compounds I-1-10 and a reducing agent Et3SiH are subjected to selective reduction reaction under mild conditions under the action of a catalyst AlCl3 to obtain C-3 allylic position various substituted ether compounds II-1-10, and the yield is 65-97% (see figure 1 and table 1).

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for preparing pharmaceutical intermediates, specifically a method for selectively reducing ketal (acetal) to prepare phenoxy intermediates. Background Technology

[0002] Oseltamivir phosphate, marketed as Tamiflu, is a highly potent neuraminidase inhibitor and a first-line drug for the treatment and prevention of influenza A and B. Its chemical name is (3... R 4 R 5 S 4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate. The market demand for oseltamivir phosphate is enormous, especially during flu season or pandemics; therefore, developing efficient, economical, environmentally friendly synthetic routes suitable for large-scale industrial production is of significant strategic and economic importance.

[0003] The industrial synthesis of Tamiflu generally uses shikimic acid, a natural product, as the starting material. Shikimic acid undergoes chemical reactions such as esterification and protection to generate a key epoxy intermediate—the Roche epoxy intermediate (which is now commercially available). Roche has successively developed three synthetic routes for preparing Tamiflu from this epoxy intermediate, using different nitrogen nucleophiles to selectively open the ring, and through multiple steps, as shown below. In Roche's earliest original industrial synthetic route in 1999 (as shown in synthetic route 1 below), the epoxy intermediate underwent six steps of reaction to obtain Tamiflu: azid ring-opening, Staudinger reduction to aziridine, azid ring-opening again, amino acetylation, and azid reduction to form a salt, with a yield of 32.3% (see J. Org. Process Res.Dev. 1999, 3(4), 266-274; J. Org. Chem. 1998, 63, 4545-4550.). Because this route has a low yield and uses hazardous chemicals such as sodium azide, trimethylphosphine, and trifluoromethanesulfonic acid, especially sodium azide which is highly toxic and explosive, industrial production poses significant risks. To avoid using azide reagents, in 2001, Roche used allylamine to ring-open the epoxy intermediate (as shown in synthetic route 2 below), obtaining Tamiflu in 10 steps with a yield of 34.7% (see J. Org. Chem. 2001, 66, 2044.). In 2004, Roche used tert-butylamine to ring-open the epoxy compound (as shown in synthetic route 3 below), and then used diallylamine to ring-open the aziridine compound, obtaining Tamiflu in 11 steps with a yield of 58.7% (see J. Org. Process Res. Dev. 2004, 8, 86.). The latter two synthetic routes avoid the use of sodium azide, but the routes are longer and more complicated.

[0004]

[0005] Roche epoxy compounds, as key intermediates in the synthesis of Tamiflu, have a relatively simple structure, but they contain a six-membered ring and three chiral centers. Therefore, the synthesis of these epoxy compounds presents certain challenges. Current domestic and international literature reports primarily using quinic acid and shikimic acid as raw materials to prepare Roche epoxy intermediates (see J. Org. Chem., Vol. 63, No. 13, 1998, 4547; J. Org. Process Res. Dev. 1999, 3(4), 266-274).

[0006]

[0007] As shown in the two Roche epoxy intermediate synthesis routes above, the key steps affecting product yield and purity are the selective reductive ring-opening of cyclic ketals and intramolecular epoxidation under alkaline conditions. The latter process is relatively safe and mature, while the selective reductive ring-opening of cyclic ketals presents challenges such as demanding reaction temperatures and the high environmental and human hazards posed by the reducing agents and catalysts used. Firstly, the catalyst used in the quinic acid route, trimethyl trifluoromethanesulfonate (TMSOTf), is extremely expensive, and the reducing agent, dimethyl sulfide boronate complex (BMS), has a strong odor and high toxicity, leading to high costs and risks in large-scale production. Secondly, the catalyst TiCl4 selected in the shikimic acid route is a highly Lewis acidic and corrosive liquid. It rapidly fumes upon contact with air and undergoes violent hydrolysis upon contact with water, releasing large amounts of hydrogen chloride gas and heat, and generating white TiO2 particles that are easily inhaled and remain in the lungs. Furthermore, excess TiCl4 must be quenched by slowly adding large amounts of ice water or buffer solution, a process that generates massive amounts of titanium- and chloride-containing acidic wastewater. Subsequent treatment steps are cumbersome, leading to high costs for waste treatment and an environmentally unfriendly process. In addition, the reaction needs to be carried out at -35 degrees Celsius, significantly increasing equipment investment costs and energy consumption. Therefore, to synthesize Roche epoxy intermediates efficiently and safely, the selective reduction of ketals must be improved.

[0008] This patent reveals a milder, safer, more economical, and environmentally friendly selective reduction method for ketals. It replaces the original TiCl4 with a Lewis acid catalyst, AlCl3, and employs a hydrosilylation reduction method at 0–40 °C, resulting in a series of 5- O Ethyl methanesulfonyl shikimate acetal (acetal) can be regioselectively reduced to ether compounds with various alkoxy substitutions at the C-3 allyl position. Inexpensive and environmentally friendly AlCl3, as a Lewis acid catalyst, is more stable in air than TiCl4, releases less HCl gas during open-air dehumidification, is safer to use, and leaves no TiO2 residue. Furthermore, during post-treatment, we use an appropriate amount of 3N~6N hydrochloric acid to maintain the pH at 1~2, ensuring complete conversion of AlCl3 to soluble aluminum chloride (AlCl3). . The use of 6H₂O avoids the formation of poorly soluble aluminum hydroxide colloids, simplifying post-processing procedures. This patent provides a better option for the economical, safe, and green industrial production of Roche epoxy intermediates. Summary of the Invention

[0009] This invention provides a selective reduction method for ketals (acetals) used to prepare oxyacetyl phosphate intermediates. Compared with existing reduction methods, it has advantages such as cheaper and safer catalysts, milder reaction temperatures, simpler and easier operation, and better economic benefits. Therefore, it provides a new method for the synthesis of oseltamivir phosphate drugs and broadens new ideas.

[0010] To achieve the objective of this invention, the following technical means are employed: 5- O Ethyl methanesulfonyl shikimate reacts with various ketones and aldehydes to form ketals or acetals, which dissolve in a suitable solvent. Following AlCl3 catalysis and reduction with a silane reagent at a suitable temperature, a regioselective reduction reaction occurs, yielding various alkylated 5-methyl ethers at the C-3 allyl position. O - Ethyl methanesulfonyl shikimate product.

[0011] The specific implementation steps of this invention are described as follows: First, 5- O Ethyl methanesulfonyl shikimate ketal (acetal) (i.e., compounds I-1~10) was dissolved in 10~20 times (v / v) of dichloromethane. 1.3~3.8 molar equivalents of AlCl3 were added, followed by 1.0~3.0 molar equivalents of Et3SiH. The reaction was carried out at 0~40 °C for 0.5~12 h. After the reaction was complete, 6~10 times (v / v) of 3N HCl was added, and the mixture was stirred for 10 min. After extraction and separation, the aqueous phase was washed 2~3 times with dichloromethane. The combined organic phases were washed 1~2 times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and subjected to column chromatography or recrystallization to obtain an oily or white solid product (i.e., compounds II-1~10), with a yield of 65%~97%.

[0012] This invention is applicable to various 5- O The selective reduction of ethyl methanesulfonyl shikimate acetal (acetal) was tested, and the results are shown in Table 1 below.

[0013] Table 1: Selective reduction of compounds I-1~10 Attached Figure Description

[0014] Figure 1 For 5- O -Structural diagram of ethyl methanesulfonyl shikimate ketal (acetal) and its selective reduction product Implementation Cases

[0015] The following examples further illustrate the content of the present invention, but the examples do not affect the scope of protection of the present invention.

[0016] Example 1 (3 R 4 R 5 R Preparation of ethyl 3-(1-ethylpropoxy)-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-1): 3,4- O -Isopentyl-5-O Ethyl methanesulfonyl shikimate, compound (I-1) (1.0000 g, 2.8702 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, anhydrous AlCl3 (1.148 g, 8.6105 mmol) and Et3SiH (0.4339 g, 3.7312 mmol) were added sequentially at room temperature, and the reaction was carried out at 40 °C for 2.0–4.0 h. Next, 6 mL of 3N HCl was added at room temperature, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.75 g of a yellowish-white solid (which recrystallized to a white solid), compound (II-1), with a yield of 75%. The characterization and spectroscopic data of compound (II-1) are as follows: [α] D 20 = -131.1° ( c 1.22, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 6.79 (dt, J = 3.6, 1.9 Hz, 1H), 4.96 (dt, J= 6.7, 4.8 Hz, 1H), 4.39 (d, J = 5.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.76(dd, J = 6.6, 4.4 Hz, 1H), 3.34 (p, J = 5.7 Hz, 1H), 2.98 (s, 3H), 2.85 (ddt,J = 18.7, 4.6, 2.1 Hz, 1H), 2.62 - 2.47 (m, 2H), 1.54 - 1.45 (m, 4H), 1.24(t, J = 7.2 Hz, 3H), 0.84 (td, J = 7.5, 6.3 Hz, 6H). 13 C NMR (101 MHz, CDCl3 δ164.80, 136.31, 127.26, 81.80, 74.55, 72.72, 63.67, 60.05, 37.63, 27.55,24.95, 24.82, 13.16, 8.55, 8.40.

[0017] Example 2 (3 R 4 R 5R Preparation of ethyl 3-(1-methylethoxy)-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-2): 3,4- O -Isopropylidene-5- O Ethyl methanesulfonyl shikimate, compound (I-2) (1.0000 g, 3.1215 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.8324 g, 6.2430 mmol) and Et3SiH (0.7259 g, 6.2430 mmol) were added sequentially. The reaction was continued under ice bath conditions for 0.5–2.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.95 g of a pale yellow oil, compound (II-2), with a yield of 95%. The characterization and spectral data of compound (II-2) are as follows: [α] D 20 = -112.5° ( c 0.85, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 6.79 (tt, J = 3.9, 1.9 Hz, 1H), 4.97 - 4.83(m, 1H), 4.23 - 4.08 (m, 3H), 3.90 - 3.75 (m, 2H), 3.01 (d, J = 22.2 Hz, 3H), 2.94 (ddt, J = 18.4, 5.4, 1.6 Hz, 1H), 2.72 (d, J = 6.5 Hz, 1H), 2.50 - 2.40(m, 1H), 1.23 (td, J = 7.1, 1.5 Hz, 3H), 1.17 (d, J = 1.8 Hz, 3H), 1.16 (d, J = 1.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.63, 133.90, 128.43, 77.06, 71.08, 69.73, 67.42, 60.16, 37.61, 28.36, 22.01, 21.36, 13.18.

[0018] Example 3 (3 R 4 R 5 R Preparation of ethyl 1-(1-cyclopentoxy)-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-3): 3,4- O -Cyclopentyl-5- O Ethyl methanesulfonyl shikimate, compound (I-3) (1.0000 g, 2.8869 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.6736 g, 5.0521 mmol) and Et3SiH (0.5035 g, 4.3304 mmol) were added sequentially. The reaction was continued under ice bath conditions for 1.5–2.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a milky white oily crude product. Rapid column chromatography yielded 0.90 g of a colorless, transparent oily substance, compound (II-3), in 90% yield. The characterization and spectroscopic data of compound (II-3) are as follows: [α] D 20 = -131.2° ( c 0.65, CHCl3). 1H NMR (400 MHz, CDCl3) δ 6.79 (dt, J = 3.6, 1.8 Hz, 1H), 4.94 (dt, J= 7.2, 5.3 Hz, 1H), 4.39 (p, J = 4.2 Hz, 1H), 4.14 (dtd, J = 13.5, 6.7, 6.2,2.9 Hz, 3H), 3.69 (dd, J = 7.3, 4.4 Hz, 1H), 2.98 (s, 3H), 2.86 (ddd, J =18.5, 4.6, 2.2 Hz, 1H), 2.58 (d, J = 6.9 Hz, 1H), 2.50 (ddt, J = 18.5, 5.7,1.6 Hz, 1H), 1.77 - 1.67 (m, 2H), 1.62 (dtd, J = 10.7, 7.5, 3.2 Hz, 4H), 1.55- 1.46 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.73,135.78, 127.68, 81.50, 74.84, 73.48, 63.69, 60.09, 37.50, 31.85, 31.82,28.09, 22.25, 22.22, 13.16.

[0019] Example 4 (3 R 4 R 5 R Preparation of ethyl 1-cyclohexyloxy)-3-(1-cyclohexyloxy)-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-4): 3,4- O -Cyclohexyl-5- OEthyl methanesulfonyl shikimate, compound (I-4) (1.0000 g, 2.7745 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (1.1099 g, 8.3236 mmol) and Et3SiH (0.4839 g, 4.1618 mmol) were added sequentially. The reaction was continued under ice bath conditions for 1.0–2.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 0.97 g of a white solid, compound (II-4), with a yield of 97%. The characterization and spectral data of compound (II-4) are as follows: [α] D 20 = -120.9° ( c 0.91, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 6.78 (dt, J = 3.9, 1.9 Hz, 1H), 4.96 - 4.84(m, 1H), 4.16 (ddt, J = 14.2, 7.1, 3.0 Hz, 3H), 3.85 (ddd, J = 8.1, 6.5, 4.5Hz, 1H), 3.52 - 3.37 (m, 1H), 3.01 (d, J = 22.0 Hz, 3H), 2.97 - 2.89 (m, 1H), 2.75 (d, J = 6.5 Hz, 1H), 2.50 - 2.40 (m, 1H), 1.94 - 1.79 (m, 2H), 1.77 -1.64 (m, 2H), 1.35 - 1.11 (m, 9H). 13 C NMR (101 MHz, CDCl3) δ 164.66, 134.11,128.31, 77.10, 77.01, 69.65, 67.42, 60.16, 37.61, 32.15, 31.50, 28.30, 24.46,23.03, 23.00, 13.19.

[0020] Example 5 (3 R 4 R 5 RPreparation of ethyl 1-cyclohexene-1-carboxylate (II-5), i.e., compound (II-5): 3,4- O -benzyl-5- O Ethyl methanesulfonyl shikimate, compound (I-5) (1.0000 g, 2.7144 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.8325 g, 6.2432 mmol) and Et3SiH (0.7260 g, 6.2432 mmol) were added sequentially. The reaction was continued under ice bath conditions for 0.5–1.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.85 g of a colorless, transparent oil, compound (II-5), with a yield of 85%. The characterization and spectral data of compound (II-5) are as follows: [α] D 20 = -59.5° ( c 0.75, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.32 - 7.26 (m, 5H), 6.81 (dt, J = 3.8, 1.8Hz, 1H), 4.93 (dt, J = 8.1, 5.9 Hz, 1H), 4.70 - 4.56 (m, 2H), 4.23 - 4.08 (m,3H), 3.92 (ddd, J = 8.2, 6.1, 4.2 Hz, 1H), 3.00 (s, 3H), 2.95 (ddt, J = 18.4,5.4, 1.5 Hz, 1H), 2.75 (d, J = 6.4 Hz, 1H), 2.46 (ddt, J = 18.4, 6.5, 1.5 Hz,1H), 1.23 (t, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.50, 136.12,132.82, 129.02, 127.66, 127.30, 127.04, 76.73, 71.51, 71.23, 67.26, 60.21,37.58, 28.49, 13.16.

[0021] Example 6 (3 R 4 R 5 R Preparation of ethyl 3-p-methylbenzoxy-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-6): 3,4- O -p-methylbenzyl-5- O Ethyl methanesulfonyl shikimate, compound (I-6) (1.0000 g, 2.6149 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.4358 g, 3.2686 mmol) and Et3SiH (0.4561 g, 3.922 mmol) were added sequentially. The reaction was continued under ice bath conditions for 3.0–5.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.82 g of a white solid, compound (II-6), in 82% yield. The characterization and spectral data of compound (II-6) are as follows: [α] D 20 = -131.3° ( c 1.24, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.21 - 7.15 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.81 (dt, J = 3.9, 1.9 Hz, 1H), 4.91 (ddd, J = 8.2, 6.5, 5.4 Hz, 1H),4.67 - 4.51 (m, 2H), 4.21 - 4.09 (m, 3H), 3.90 (ddd, J = 8.1, 6.4, 4.4 Hz,1H), 3.00 (s, 3H), 3.01 - 2.90 (m, 4H), 2.73 (d, J = 6.4 Hz, 1H), 2.46 (dddd,J = 18.5, 6.5, 2.1, 1.3 Hz, 1H), 1.25 - 1.21 (m, 3H). 13C NMR (101 MHz, CDCl3)δ 165.55, 138.20, 134.09, 133.94, 129.99, 129.37, 128.22, 77.85, 72.30,72.12, 68.27, 61.21, 38.61, 29.53, 21.21, 14.19.

[0022] Example 7 (3 R 4 R 5 R Preparation of ethyl 1-cyclohexene-1-carboxylate (II-7), namely 3-p-fluorobenzoxy-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate: 3,4- O -p-Fluorophenyl-5- O Ethyl methanesulfonyl shikimate, compound (I-7) (1.0000 g, 2.5881 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.6384 g, 4.7879 mmol) and Et3SiH (0.5116 g, 4.3997 mmol) were added sequentially. The reaction was continued under ice bath conditions for 2.0–4.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.82 g of a white solid, compound (II-7), in 82% yield. The characterization and spectral data of compound (II-7) are as follows: [α] D 20 = -134.8° ( c 1.21, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.31 - 7.23 (m, 2H), 7.03 - 6.93 (m, 2H), 6.79 (dt, J = 3.9, 1.9 Hz, 1H), 4.99 - 4.88 (m, 1H), 4.67 - 4.53 (m, 2H),4.22 - 4.09 (m, 3H), 3.93 (ddd, J = 8.1, 6.3, 4.3 Hz, 1H), 3.02 (s, 3H), 2.99- 2.90 (m, 1H), 2.68 (d, J = 6.3 Hz, 1H), 2.52 - 2.41 (m, 1H), 1.23 (t, J =7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.49, 163.88, 161.42, 133.69, 133.01(d, J = 3.3 Hz), 130.13, 129.87 (d, J = 8.2 Hz), 115.69, 115.48, 77.64,72.62, 71.56, 68.32, 61.27, 38.63, 29.49, 14.18.

[0023] Example 8 (3 R 4 R 5 R Preparation of ethyl 3-p-chlorobenzoxy-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-8): 3,4- O -p-chlorobenzyl-5- OEthyl methanesulfonyl shikimate, compound (I-8) (1.0000 g, 2.4824 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.4634 g, 3.4753 mmol) and Et3SiH (0.3752 g, 3.2271 mmol) were added sequentially. The reaction was continued under ice bath conditions for 2.0–4.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.84 g of a white solid, compound (II-8), in 84% yield. The characterization and spectral data of compound (II-8) are as follows: [α] D 20 = -141.3° ( c 1.17, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.4 Hz, 2H), 7.24 - 7.18 (m,2H), 6.79 (dt, J = 3.9, 1.9 Hz, 1H), 4.94 (dt, J = 8.0, 6.0 Hz, 1H), 4.71 -4.52 (m, 2H), 4.26 - 4.06 (m, 3H), 3.94 (ddd, J = 8.1, 6.4, 4.3 Hz, 1H), 3.02(s, 3H), 2.96 (ddt, J = 18.5, 5.5, 1.6 Hz, 1H), 2.68 (d, J = 6.3 Hz, 1H),2.47 (ddt, J = 18.5, 6.6, 1.6 Hz, 1H), 1.23 (t, J = 7.2 Hz, 3H). 13 C NMR (101MHz, CDCl3) δ 165.47, 135.70, 134.11, 133.58, 130.21, 129.33, 128.84, 77.58,72.77, 71.48, 68.34, 61.29, 38.64, 29.50, 14.19.

[0024] Example 9 (3 R 4 R 5R Preparation of ethyl 3-p-bromobenzoxy-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylic acid, i.e., compound (II-9): 3,4- O -p-bromophenylmethyl-5- O Ethyl methanesulfonyl shikimate, compound (I-9) (1.0000 g, 2.2356 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under ice-water bath conditions, anhydrous AlCl3 (0.5068 g, 3.8006 mmol) and Et3SiH (0.4679 g, 4.0241 mmol) were added sequentially. The reaction was continued under ice bath conditions for 2.0–4.0 h until the reactants were completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.85 g of a white solid, compound (II-9), in 85% yield. The characterization and spectral data of compound (II-9) are as follows: [α] D 20 = -111.1° (c 1.23, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 7.56 - 7.46 (m, 2H), 7.25 - 7.20 (m, 2H), 6.86 (dt, J = 3.8, 1.8 Hz, 1H), 5.07 - 4.96 (m, 1H), 4.74 - 4.60 (m, 2H), 4.32 - 4.16 (m, 3H), 4.02 (d, J = 7.1 Hz, 1H), 3.09 (s, 3H), 3.03 (ddt, J =18.4, 5.2, 1.6 Hz, 1H), 2.78 - 2.66 (m, 1H), 2.54 (ddt, J = 18.4, 6.5, 1.5Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.46, 136.21,133.56, 131.80, 130.23, 129.62, 122.24, 77.56, 72.80, 71.51, 68.35, 61.29,38.64, 29.50, 14.20.

[0025] Example 10 (3 R 4 R 5 R Preparation of ethyl 3-p-nitrobenzoxy-4-hydroxy-5-[(methanesulfonyl)oxy]-1-cyclohexene-1-carboxylate, i.e., compound (II-10): 3,4- O -p-nitrophenylmethyl-5- O Ethyl methanesulfonyl shikimate, compound (I-10) (1.000 g, 2.4190 mmol), was placed in a 50 mL single-necked flask and dissolved in 10 mL of dichloromethane. Then, under an ice-water bath, anhydrous AlCl3 (1.2257 g, 9.1921 mmol) and Et3SiH (0.5626 g, 4.8379 mmol) were added sequentially. The reaction was carried out under ice bath conditions for 1 h, and then continued overnight at room temperature. The reactants were still not completely reacted. 6 mL of 3N HCl was added, and the mixture was stirred for 10 min. The mixture was extracted and separated. The aqueous phase was extracted twice with dichloromethane, and the organic phases were combined. The resulting organic phase was washed twice with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. Rapid column chromatography yielded 0.65 g of a yellowish-white solid, compound (II-10), with a yield of 65% and a 26% recovery of the starting material. The characterization and spectral data of compound (II-10) are as follows: [α] D 20 = -107.7° ( c 1.05, CHCl3). 1 H NMR (400 MHz, CDCl3) δ 8.34 - 8.18 (m, 2H), 7.63 - 7.49 (m, 2H), 6.90 (dq, J = 6.3, 4.4, 3.1 Hz, 1H), 5.06 (dt, J = 7.9, 5.8 Hz, 1H), 4.85 (s,2H), 4.39 - 4.29 (m, 1H), 4.29 - 4.18 (m, 2H), 4.09 (ddd, J = 7.8, 5.8, 4.1Hz, 1H), 3.11 (s, 3H), 3.09 - 2.99 (m, 1H), 2.80 (d, J = 5.9 Hz, 1H), 2.62 -2.49 (m, 1H), 1.35 - 1.28 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 165.38, 147.65,144.73, 133.13, 130.54, 128.03, 123.82, 77.29, 73.58, 71.08, 68.53, 61.38,38.66, 29.53, 14.19。

Claims

1. A 5- O A selective reduction method for ethyl methanesulfonyl shikimate ketal (acetal), which involves reacting various ketones and aldehydes with 5- O Using the ketal (acetal) obtained from the reaction of ethyl methanesulfonyl shikimate as a reactant, a selective reduction reaction is carried out under the action of a metal catalyst to give the corresponding allyl-substituted (C-3-position) ether compound, characterized in that... The following are the operating steps: Under an ice water bath, 5- O Ethyl methanesulfonyl shikimate ketal or acetal (labeled as compounds I-1~10) is dissolved in a polar solvent, and 1.3~3.8 equivalents of AlCl3 are added as a catalyst, followed by 1.0~3.0 equivalents of Et3SiH as a reducing agent. The reaction is carried out at a suitable temperature for 0.5~12 h to obtain (3R,4R,5R)-3- O -Various alkyl-5- O - Ethyl methanesulfonyl shikimate (labeled as compound II-1~10).

2. The preparation method according to claim 1, characterized in that... The polar solvent used in the operation steps is one of chloroform and dichloroform, preferably dichloroform.

3. The preparation method according to claim 1, characterized in that... The catalysts used in the operation steps are ZnCl2 and BF3. . One of OEt2 and AlCl3, preferably AlCl3.

4. The preparation method according to claim 1, characterized in that... The appropriate temperature for the operation is 0~40℃.

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