Preparation method of liflozin intermediate compound

Abstract

The invention provides a preparation method of a liflozin intermediate compound, the structure of the liflozin intermediate compound is shown as a compound I. The preparation method of the liflozin intermediate compound comprises the following steps: step 1, carrying out Grignard reaction on metal magnesium and a compound IV to obtain a compound III; step 2, carrying out nucleophilic addition and deprotection reaction on the compound III and a compound V to obtain a compound II; and step 3, carrying out methylation reaction on the compound II to obtain a compound I. The preparation method of the liflozin intermediate compound provided by the invention is mild in reaction condition, high in atom utilization rate, high in yield, high in product quality and small in waste salt and waste residue amount, and solves the production problems of high material cost, harsh reaction conditions, low atom utilization rate and the like in the traditional process.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and relates to a gliflozin intermediate compound, and in particular to a preparation method of the gliflozin intermediate compound. Background Art

[0002] Gliflozin is a type of hypoglycemic drug, including empagliflozin and bexagliflozin, which lowers blood sugar levels by inhibiting the reabsorption of glucose by the renal tubules and promoting urinary sugar excretion.

[0003] Empagliflozin was originally developed by Boehringer Ingelheim and later co-developed with Eli Lilly as an SGLT2 inhibitor for the treatment of type 2 diabetes. The drug was first approved for marketing by the European Medicines Agency (EMA) on May 22, 2014, approved for marketing by the U.S. FDA on August 1, 2014, approved for marketing by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) on December 26, 2014, and approved for marketing in China by CFDA on September 21, 2017. The trade name is The structural formula is as follows:

[0004]

[0005] Bexagliflozin is an SGLT2 inhibitor developed and approved for the treatment of type 2 diabetes by TheracosBio, a US biopharmaceutical company. The drug was approved by the US FDA in December 2022 for the treatment of feline diabetes. It is also the first SGLT2 inhibitor approved by the FDA for any animal species. The trade name is Then on January 23, 2023, it was approved by the US FDA for use in conjunction with diet and exercise to improve blood sugar control in patients with type 2 diabetes. The trade name is The structural formula is as follows:

[0006]

[0007] At present, the synthesis methods of this series of drugs reported in domestic and foreign literature and patents are mainly the following:

[0008] Referring to the invention patents with publication numbers CN100534997C and CN101479287B, the synthetic route of dapagliflozin (originally developed by AstraZeneca) is as follows:

[0009] Method 1:

[0010]

[0011] Specifically, (5-bromo-2-chlorophenyl) (4-ethoxyphenyl) methane is used as the raw material, and the target product is obtained through lithium halogen exchange, nucleophilic addition, methylation, demethoxy reduction, acetyl protection, deacetylation protection (or saponification) and solvate formation. The key reaction steps are lithium halogen exchange and nucleophilic addition. This route has fewer reaction steps and a high overall yield, but it uses an expensive reagent, n-butyl lithium, and needs to be reacted at ultra-low temperatures (-70 to -80°C), which has problems such as high cost and harsh reaction conditions.

[0012] With reference to the invention patents with publication numbers CN101193903B and CN102549005B, the synthetic route of empagliflozin (originally developed by Boehringer Ingelheim) is as follows:

[0013] Method:2:

[0014]

[0015] Specifically, compound V.1 ((5-iodo-2-chlorophenyl) [4-[[(3S)-tetrahydro-3-furanyl] oxy] phenyl] methane) is used as a raw material, and the target product is obtained through the reaction steps of Grignard exchange of isopropyl magnesium chloride-lithium chloride complex, nucleophilic addition, hydrolysis, methylation and demethoxylation reduction. The key reaction steps are Grignard exchange and nucleophilic addition. This route uses isopropyl magnesium chloride-lithium chloride complex instead of the expensive reagent n-butyl lithium, and increases the reaction temperature of nucleophilic addition from ultra-low temperature (-70 to -80°C) to (-20 to -30°C), which has the advantages of mild reaction conditions; however, the use of iodide as a raw material is also expensive, and the use of isopropyl magnesium chloride-lithium chloride complex for Grignard exchange has a low atomic utilization rate.

[0016] Referring to the invention patents with publication numbers CN101790311B and CN102933592B, the first generation synthesis route of bexagliflozin (originally developed by Theracos Bio Pharmaceuticals, Inc., USA) is as follows:

[0017] Method 3:

[0018]

[0019] Method 3 is similar to method 1, specifically: compound 5D ((5-bromo-2-chlorophenyl) [4-(2-cyclopropyloxyethoxy) phenyl] methane) is used as a raw material, and the target product is obtained through lithium halogen exchange, nucleophilic addition, methylation, demethoxy reduction and diproline formation. The key reaction steps are lithium halogen exchange and nucleophilic addition. This route still uses the expensive reagent n-butyl lithium, and needs to be reacted at ultra-low temperature (-70 to -80°C), which has problems such as high cost and harsh reaction conditions.

[0020] Referring to the invention patent with publication number CN104334568A, the second-generation synthesis route of bexagliflozin originally developed by Theracos Bio Pharmaceuticals of the United States is as follows:

[0021] Method 4:

[0022]

[0023] Method 4 is similar to method 2, specifically: using compound 1 ((5-iodo-2-chlorophenyl) [4-(2-cyclopropyloxyethoxy) phenyl] methane) as a raw material, the target product is obtained through the reaction steps of Grignard exchange of isopropyl magnesium chloride-lithium chloride complex, nucleophilic addition, hydrolysis, methylation, demethoxy reduction, diproline complex formation, alkali release and crystallization. The key reaction steps are Grignard exchange and nucleophilic addition. This route uses isopropyl magnesium chloride-lithium chloride complex instead of expensive reagent n-butyl lithium, and the reaction temperature of nucleophilic addition is increased from ultra-low temperature (-70 to -80°C) to (-15 to -30°C), which has the advantages of mild reaction conditions; however, the iodide is used as a raw material, which is also expensive, and the atom utilization rate of isopropyl magnesium chloride-lithium chloride complex for Grignard exchange is not high.

[0024] The structure of compound I is shown below:

[0025]

[0026] Ib and Ic in compound I are key intermediates for the synthesis of gliflozin drugs, empagliflozin and bexagliflozin, respectively. The synthetic routes of the intermediates are of great significance for the preparation of gliflozin drugs.

[0027] The current synthesis process of Compound I has problems such as high material cost, harsh reaction conditions and low atom utilization. Therefore, a strategy is needed to improve it and select a green, environmentally friendly and low-cost intermediate synthesis route. Summary of the invention

[0028] The present invention aims at the problems existing in the prior art and provides a method for preparing a levofloxacin intermediate compound. The present invention prepares a Grignard reagent, performs nucleophilic addition and deprotection reaction with hydroxyl-protected gluconolactone, and then performs a methylation reaction to obtain a levofloxacin intermediate compound. The method has the advantages of mild reaction conditions, high atom utilization, small amount of waste salt and waste residue, high yield and high product quality, and solves the production problems of high material cost and harsh reaction conditions of traditional processes.

[0029] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0030] In the first aspect, the present invention provides a method for preparing a levitra intermediate compound, characterized in that the structure of the levitra intermediate compound is as shown in Compound I:

[0031]

[0032] The preparation method of the intermediate compound of the linaloxone class comprises the following steps:

[0033] Step 1: Metal magnesium and compound IV are subjected to a Grignard reaction to obtain compound III. The synthesis route is as follows:

[0034]

[0035] Step 2, compound III and compound V are subjected to nucleophilic addition and deprotection reaction to obtain compound II. The synthetic route is as follows:

[0036]

[0037] Step 3, subjecting compound II to a methylation reaction to obtain compound I. The synthetic route is as follows:

[0038]

[0039] In the compounds I-IV, R is selected from fluorine atoms,

[0040] In the compounds III and IV, X is selected from chlorine, bromine or iodine;

[0041] In the compound V, R 1 is a protecting group for the hydroxyl group, selected from one of trimethylsilyl, benzyl and acyl.

[0042] In the compounds III and IV, X is preferably bromine or iodine; in the compound V, R 1 Preferred is trimethylsilyl.

[0043] In the step 1, the temperature of the Grignard reaction is 0 to 55°C, preferably 0 to 35°C, and the Grignard reaction uses an anhydrous solvent, which is selected from one or more of anhydrous ether, anhydrous ethylene glycol dimethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous toluene, anhydrous xylene, anhydrous hexane, anhydrous heptane or anhydrous tetrahydrofuran, preferably anhydrous ether or anhydrous tetrahydrofuran, more preferably anhydrous tetrahydrofuran. The molar ratio of the compound IV to the magnesium metal is 1:1 to 2, preferably 1:1 to 1.5. The reaction conditions of step 1 are mild and not harsh, and there is no need to carry out at ultra-low temperatures (-70 to -80°C).

[0044] In one embodiment, the step 1 is specifically as follows: performing a Grignard reaction under inert gas protection conditions, wherein the inert gas is preferably nitrogen, dissolving compound IV in anhydrous tetrahydrofuran at room temperature to obtain a solution of compound IV, wherein the concentration of the solution of compound IV is 1 to 2 mmol / mL, preferably 1.7 mmol / mL; slowly dropping the solution of compound IV into a 4.0 to 4.2 mmol / mL anhydrous tetrahydrofuran system of metallic magnesium at 0 to 5°C, wherein the dropping time is 1 to 3 hours, preferably 2 hours, and preferably slowly adding the solution of compound IV to a system of metallic magnesium and anhydrous tetrahydrofuran at room temperature to initiate the reaction; transferring the reaction system to 30 to 35°C for reaction for 1 to 3 hours, preferably for reaction for 2 hours, to obtain a solution of compound III.

[0045] In the step 2, the temperature of the nucleophilic addition and deprotection reaction is -30 to 30 ° C, and the nucleophilic addition reaction adopts anhydrous solvent, and the anhydrous solvent is selected from one or more of anhydrous ether, anhydrous ethylene glycol dimethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous toluene, anhydrous xylene, anhydrous hexane, anhydrous heptane or anhydrous tetrahydrofuran, preferably anhydrous ether, anhydrous tetrahydrofuran, a mixture of anhydrous ether and anhydrous toluene, anhydrous tetrahydrofuran and anhydrous toluene. One of the mixture is more preferably anhydrous tetrahydrofuran and anhydrous toluene. The ratio of the two solvents in the mixture is not limited here. In one embodiment, the volume ratio of anhydrous tetrahydrofuran and anhydrous toluene in the mixture of anhydrous tetrahydrofuran and anhydrous toluene is 150:750. The deprotection reaction adopts dilute acid, and the dilute acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, formic acid, acetic acid, oxalic acid or citric acid, preferably acetic acid or citric acid, more preferably acetic acid. In one embodiment, the acetic acid is an acetic acid aqueous solution, and the mass percentage of the acetic acid aqueous solution is preferably 7.5%. The molar ratio of the compound III to the compound V is 1:1-1.5, preferably 1:1-1.2.

[0046] In one embodiment, the step 2 is specifically: mixing the solution of compound III obtained in step 1 and anhydrous toluene in a volume ratio of 1:2; slowly adding 0.5-0.6 mmol / mL toluene solution of compound V for nucleophilic addition reaction, the molar ratio of III to compound V is 1:1-1.5, preferably 1:1-1.2, the temperature of the nucleophilic addition reaction is -30--20°C, and the reaction time is 1-3h, preferably 2h; after the reaction, adding dilute acid for deprotection reaction, the dilute acid is acetic acid aqueous solution, the mass percentage of the acetic acid aqueous solution is preferably 7.5%, the temperature of the deprotection reaction is 20-30°C, the reaction time is 0.5-1h, and after the reaction, it is preferably concentrated to obtain a concentrate of compound II.

[0047] In step 3, the temperature of the methylation reaction is room temperature, and the methylation reaction uses an acidic reagent and methanol. The acidic reagent can be any commonly used type in the art. Preferably, the methylation reaction uses hydrochloric acid and methanol.

[0048] In one embodiment, in the compound I, R is selected from a fluorine atom, and the method for preparing the levitra intermediate compound preferably further comprises: using s-3-hydroxytetrahydrofuran to carry out a nucleophilic addition reaction with the levitra intermediate compound I under alkaline conditions, and the nucleophilic addition reaction temperature is preferably 0 to 15°C.

[0049] In one embodiment, step 3 is specifically: methylating the concentrate of compound II obtained in step 2 with hydrochloric acid and methanol, wherein the molar ratio of compound II to hydrochloric acid is 1:0.1-10, preferably 1:0.1-2, the molar ratio of hydrochloric acid to methanol is 180-200:1, preferably 185-190:1, the methylation reaction time is 15-25h, preferably 20h, the reaction temperature is room temperature, after the reaction is completed, the pH of the system is adjusted to neutral or weakly alkaline, the solvent is distilled off, and tetrahydrofuran-heptane crystallization is used to obtain compound I.

[0050] Compared with the prior art, the present invention has the following beneficial effects: the method for preparing a levitra intermediate compound provided by the present invention has mild reaction conditions, high atom utilization, high yield, high product quality, and small amount of waste salt and waste residue, which solves the production problems of high material cost, harsh reaction conditions, and low atom utilization in traditional processes. DETAILED DESCRIPTION

[0051] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0052] The following sources of raw materials are provided for illustrative purposes:

[0053] Magnesium chips: industrial grade, Shanxi Fuhengdi Metal Materials Co., Ltd.;

[0054] Anhydrous tetrahydrofuran: industrial grade, Jiangsu Heshili New Materials Co., Ltd.;

[0055] Methanol: industrial grade, Saudi Arabian Oil Company;

[0056] (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran: reagent grade, purity 98%, MacLean, Shanghai MacLean Biochemical Technology Co., Ltd.;

[0057] TMS-GDL: (2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone): reagent grade, purity 96%, Anaiji Chemical, Anhui Zesheng Technology Co., Ltd.;

[0058] Acetic acid: industrial grade, Jiangsu Suopu Chemical Co., Ltd.;

[0059] Hydrochloric acid: industrial grade or refined grade, Wanhua Chemical (Ningbo) Chlor-Alkali Co., Ltd.;

[0060] s-3-Hydroxytetrahydrofuran: purity>99%, Shandong Xuande Pharmaceutical Technology Co., Ltd.

[0061] Example 1: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside

[0062] Step 1: Preparation of 4-chloro-3-[4-[(3S)-tetrahydro-3-furanyloxy]benzyl]phenylmagnesium bromide

[0063]

[0064] The 2L four-necked bottle was replaced with nitrogen three times, and under the protection of nitrogen flow, magnesium chips 5.0g (205.7mmol), anhydrous tetrahydrofuran 50mL, anhydrous tetrahydrofuran solution of (S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran ((S)-3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran 63.2g, 171.9mmol, anhydrous tetrahydrofuran were added in sequence. The mixture was transferred to a dropping funnel (100 mL), and about 5 mL was first added dropwise to initiate the reaction. The mixture was then cooled to 0-5° C. and the remaining anhydrous tetrahydrofuran solution of 3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran was added dropwise slowly for 2 hours. After the addition was completed, the mixture was heated to 30-35° C. and kept for reaction for 2 hours to obtain a 4-chloro-3-[4-[(3S)-tetrahydro-3-furanyloxy]benzyl]phenylmagnesium bromide solution for use.

[0065] Step 2: Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol

[0066]

[0067] To the 4-chloro-3-[4-[(3S)-tetrahydro-3-furanyloxy]benzyl]phenylmagnesium bromide solution prepared in step 1, add 300 mL of anhydrous toluene, cool to -30 ° C, control the temperature to ≤ -20 ° C, slowly add TMS-GDL toluene solution (TMS-GDL: 90 g, 192.8 mmol, toluene: 350 mL), add dropwise for about 1 hour, control the temperature at -30 to -20 ° C, keep the reaction for 2 hours, and then add the quality control agent. The mixture was stirred for 0.5 to 1 hour. 200 g of 7.5% aqueous acetic acid solution was heated to 20-30° C. and kept warm for reaction for 0.5 to 1 hour. The low boiling point solvent was removed by distillation under reduced pressure. The liquids were separated and the organic phase was distilled under reduced pressure to remove the solvent to obtain a light yellow oily (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol concentrate.

[0068] Step 3: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-glucopyranoside

[0069]

[0070] The (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 1.8 g of hydrochloric acid was added, and the reaction was stirred at room temperature for 20 hours, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.6, and the solvent was distilled off under reduced pressure. After crystallization from tetrahydrofuran-heptane, 73.2 g of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside was obtained, with a yield (total yield of 3 steps) of 88.5% and a purity of 99.1%.

[0071] 1 HNMR (CDCl 3,400MHz)δ7.35(s,1H,4-chlorophenyl-5-CH),7.26(m,1H,4-chlorophenyl-2-CH),7.22(m,1H,4-chlorophenyl-6-CH),7.05(m,2H,4-alkoxyphenyl-2,6-CH),6.86(m,2H,4-alkoxyphenyl-3,5-CH),5.92(s,1H,α-D-glucopyranoside-4-OH),5.78(s,1H,α-D-glucopyranoside-2-OH),5.78(s,1H,α-D-glucopyranoside-3-OH),4.00(d,1H,α-D-glucopyranoside-2-CH),3.97-3.83(m,2H,S-3-aryloxytetrahydrofuran-2-CH 2 ),3.93(m,1H,S-3-aryloxytetrahydrofuran-3-CH),3.80(m,2H,CH 2 ),3.76(m,1H,α-D-glucopyranoside-6-OH),3.74-3.57(m,2H,S-3-aryloxytetrahydrofuran-5-CH 2 ),3.57(m,1H,α-D-glucopyranoside-3-CH),3.57(m,1H,α-D-glucopyranoside-4-CH),3.48(s,1H,α-D-glucopyranoside-5-CH),3.46-3.34(m,2H,α-D-glucopyranoside-6-CH 2 ),2.86(s,3H,α-D-glucopyranoside-1-OCH 3 ),1.87-1.17(m,2H,S-3-aryloxytetrahydrofuran-4-CH 2 )。

[0072] 13 CNMR(CDCl 3,100MHz)δ160.4(1C,4-alkoxyphenyl-C-4),138.0(1C,4-chlorophenyl-C-3),136.7(1C,4-chloroph enyl-C-1),135.1(1C,4-alkoxyphenyl-C-1),134.4(2C,4-chlorophenyl-C-2,4),130.1(1C,4-chlor ophenyl-C-5),130.1(2C,4-alkoxyphenyl-C-2,6),129.3(1C,4-chlorophenyl-C-6),127.0(1C,α-D- glucopyranoside-C-1),115.2(2C,4-alkoxyphenyl-C-3,5),101.0(1C,α-D-glucopyranoside-C-5),

[0073] 77.2(1C,S-3-aryloxytetrahydrofuran-C-3),76.8(1C,S-3-aryloxytetrahydrofuran-C-2),74.5(1C,α-D-glucopyranoside-C-3),72.6(1C,α-D-glucopyranosid e-C-4),69.8(1C,α-D-glucopyranoside-C-2),69.8(1C,S-3-aryloxytetrahydrofuran-C-5),61.6(1C,α-D-glucopyranoside-C-6),49.1(1C,-OCH3),38.5(1C,-CH 2 ), 22.4(1C,S-3-aryloxytetrahydrofuran-C-4).

[0074] Example 2: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside

[0075] Step 1: Preparation of 4-chloro-3-[4-[(3S)-tetrahydro-3-furanyloxy]benzyl]phenylmagnesium iodide

[0076]

[0077] The 2L four-necked bottle was replaced with nitrogen three times. Under the protection of nitrogen flow, 5.0 g (205.7 mmol) of magnesium chips, 50 mL of anhydrous tetrahydrofuran, 0.05 g of iodine and 1.0 g of 3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran were added in sequence. The temperature was raised to 55°C to initiate the reaction. The temperature was lowered to 0-5°C. An anhydrous tetrahydrofuran solution of 3-(4-(5-bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (63.2 g, 171.9 mmol, 100 mL of anhydrous tetrahydrofuran) was slowly added dropwise. The mixture was slowly added dropwise for 2 hours. After the addition was completed, the mixture was heated to 30-35°C and kept warm for 2 hours to obtain a 4-chloro-3-[4-[(3S)-tetrahydro-3-furanoxy]benzyl]phenyl magnesium iodide solution for use.

[0078] Step 2: Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol

[0079]

[0080] To the 4-chloro-3-[4-[(3S)-tetrahydro-3-furanyloxy]benzyl]phenylmagnesium iodide solution prepared in step 1, add 300 mL of anhydrous toluene, cool to -30 ° C, control the temperature to ≤ -20 ° C, slowly add TMS-GDL toluene solution (TMS-GDL: 90 g, 192.8 mmol, toluene: 350 mL), add for about 1 hour, control the temperature at -30 to -20 ° C, keep the reaction for 2 hours, and then add mass 200 g of 7.5% acetic acid aqueous solution was heated to 20-30° C. and kept warm for 0.5-1 hour. The low boiling point solvent was removed by distillation under reduced pressure. The liquids were separated and the organic phase was distilled under reduced pressure to remove the solvent to obtain a light yellow oily (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol concentrate.

[0081] Step 3: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-glucopyranoside

[0082]

[0083] The (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(((S)-3-tetrahydrofuran)oxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 1.8 g of hydrochloric acid was added, and the mixture was stirred at room temperature for 20 hours. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.6. After the solvent was removed by distillation under reduced pressure, 75.1 g of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside was obtained by crystallization from tetrahydrofuran-heptane, with a yield (total yield of 3 steps) of 89.4% and a purity of 98.7%.

[0084] Example 3: Preparation of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-pyranoglucoside

[0085] Step 1: Preparation of 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium bromide

[0086]

[0087] The 2L four-necked bottle was replaced with nitrogen three times. Under the protection of nitrogen flow, 5.0 g (205.7 mmol) of magnesium chips and 50 mL of anhydrous tetrahydrofuran were added in sequence. The anhydrous tetrahydrofuran solution of 5-bromo-2-chloro-4'-(2-cyclopropyloxyethoxy)diphenylmethane (65.6 g, 171.9 mmol of 5-bromo-2-chloro-4'-(2-cyclopropyloxyethoxy)diphenylmethane, anhydrous tetrahydrofuran, was transferred to a dropping funnel. About 5 mL was first added dropwise to initiate the reaction. Then, the temperature was lowered to 0-5°C and the remaining bromide solution was added dropwise. The solution was slowly added dropwise for 2 hours. After the addition was completed, the temperature was raised to 30-35°C and the reaction was kept warm for 2 hours to obtain a 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium bromide solution for standby use.

[0088] Step 2: Preparation of 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-glucopyranose

[0089]

[0090] To the 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium bromide solution prepared in step 1, 300 mL of anhydrous toluene was added, the temperature was lowered to -30 ° C, the temperature was controlled to ≤ -20 ° C, and TMS-GDL toluene solution (TMS-GDL: 90 g, 192.8 mmol, toluene: 350 mL) was slowly added dropwise for about 1 hour. After the addition was completed, the reaction was kept warm for 2 hours, and 200 g of acetic acid aqueous solution with a mass fraction of 7.5% was added. The temperature was raised to 20-30 ° C, and the reaction was kept warm for 0.5-1 hour. The low boiling point solvent was removed by reduced pressure distillation, the liquid was separated, and the organic phase was distilled under reduced pressure to remove the solvent to obtain a light yellow oily 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-pyranose concentrate.

[0091] Step 3: Preparation of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-glucopyranoside

[0092]

[0093] The 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-pyranose glucose concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 5.4 g of hydrochloric acid was added, and the mixture was stirred at room temperature for 18 hours. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.2, and the mixture was distilled under reduced pressure. The mixture was crystallized from tetrahydrofuran-heptane to obtain 71.3 g of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-pyranose glucoside, with a yield (total yield of 3 steps): 83.8% and a purity of 98.5%.

[0094] 1 HNMR (CDCl 3,400MHz)δ7.35(s,1H,4-chlorophenyl-5-CH),7.25(d,1H,4-chlorophenyl-2-CH),7.23(d,1H,4-chlorophenyl-6-CH),7.01(d,2H,4-alkoxyphenyl-2,6-CH),6.75(d,2H,4-alkoxyphenyl-3,5-CH),5.35(s,1H,α-D-glucopyranoside-4-OH),5.25(s,1H,α-D-glucopyranoside-2-OH),4.32(s,1H,α-D-glucopyranoside-3-OH),3.99(d,1H,α-D-glucopyranoside-2-CH),3.96(t,2H,2-cycloproxyethoxy-1-CH 2 ),3.83(m,1H,α-D-glucopyranoside-6-OH),3.76(m,2H,CH 2 ),3.56(m,2H,2-cycloproxyethoxy-2-CH 2 ),3.54(m,1H,α-D-glucopyranoside-3-CH),3.48(s,1H,α-D-glucopyranoside-4-CH),3.46(s,1H,α-D-glucopyranoside-5-CH),3.34-3.31(m,2H,α-D-glucopyranoside-6-CH 2 ),3.17(m,1H,cyclopropoxy-1-CH),2.85(s,3H,α-D-glucopyranoside-1-OCH 3 ),0.57-0.44(m,4H,cyclopropoxy-2,3-CH 2 )。

[0095] 13 CNMR(CDCl 3,100MHz)δ157.1(1C,4-alkoxyphenyl-C-4),138.4(1C,4-chlorophenyl-C-3),136.8(1C,4-chloroph enyl-C-1),134.2(1C,4-alkoxyphenyl-C-1),131.9(2C,4-chlorophenyl-C-2,4),130.2(1C,4-chlor ophenyl-C-5),129.6(2C,4-alkoxyphenyl-C-2,6),129.2(1C,4-chlorophenyl-C-6),126.9(1C,α-D- glucopyranoside-C-1),114.6(2C,4-alkoxyphenyl-C-3,5),101.0(1C,α-D-glucopyranoside-C-5),

[0096] 74.6(1C,α-D-glucopyranoside-C-3),72.6(1C,α-D-glucopyranoside-C-4),69.9(1C,α-D-glucopyranoside-C-2),69.1(1C,2-cycloproxyethoxy-C-1),67.0(1C,2-cyclopro xyethoxy-C-2),61.7(1C,α-D-glucopyranoside-C-6),53.7(1C,cyclopropoxy-C-1),49.1(1C,-OCH 3 ),38.5(1C,-CH 2 ),5.7(2C,cyclopropoxy-C-2,3).

[0097] Example 4: Preparation of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-pyranoglucoside

[0098] Step 1: Preparation of 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium iodide

[0099]

[0100] The 2L four-necked bottle was replaced with nitrogen three times. Under the protection of nitrogen flow, 6 g (246.9 mmol) of magnesium chips, 50 mL of anhydrous tetrahydrofuran, 0.05 g of iodine and 1 g of 5-bromo-2-chloro-4'-(2-cyclopropyloxyethoxy)diphenylmethane were added in sequence. The temperature was raised to 55°C to initiate the reaction. The temperature was lowered to 0-5°C. An anhydrous tetrahydrofuran solution of 5-bromo-2-chloro-4'-(2-cyclopropyloxyethoxy)diphenylmethane (64.6 g of 5-bromo-2-chloro-4'-(2-cyclopropyloxyethoxy)diphenylmethane and 100 mL of anhydrous tetrahydrofuran) was slowly added dropwise. The mixture was slowly added dropwise for 2 hours. After the addition was completed, the mixture was heated to 30-35°C and kept warm for reaction for 2 hours to obtain a 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium iodide solution for use.

[0101] Step 2: Preparation of 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-glucopyranose

[0102]

[0103] To the 4-chloro-3-[4-(2-cyclopropyloxyethoxy)benzyl]phenylmagnesium iodide solution prepared in step 1, 300 mL of anhydrous toluene was added, the temperature was lowered to -30 ° C, the temperature was controlled to ≤ -20 ° C, and TMS-GDL toluene solution (TMS-GDL: 90 g, 192.8 mmol, toluene: 350 mL) was slowly added dropwise for about 1 hour. After the addition was completed, the reaction was kept warm for 2 hours, and 200 g of acetic acid aqueous solution with a mass fraction of 7.5% was added. The temperature was raised to 20-30 ° C, and the reaction was kept warm for 0.5-1 hour. The low boiling point solvent was removed by reduced pressure distillation, the liquid was separated, and the organic phase was distilled under reduced pressure to remove the solvent to obtain a light yellow oily 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-pyranose concentrate.

[0104] Step 3: Preparation of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-glucopyranoside

[0105]

[0106] The 1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-D-pyranose glucose concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 5.4 g of hydrochloric acid was added, and the mixture was stirred at room temperature for 18 hours. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.2, and the mixture was distilled under reduced pressure. The mixture was crystallized from tetrahydrofuran-heptane to obtain 75.6 g of methyl-1-C-[4-chloro-3-[(4-(2-cyclopropyloxyethoxy)phenyl)methyl]phenyl]-α-D-pyranose glucoside, with a yield (total yield of 3 steps) of 88.8% and a purity of 99.2%.

[0107] Example 5: Preparation of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranoglucoside

[0108] Step 1: Preparation of 4-chloro-3-(4-fluorobenzyl)phenylmagnesium bromide

[0109]

[0110] The 2L four-necked bottle was replaced with nitrogen three times. Under the protection of nitrogen flow, 5.0 g (205.7 mmol) of magnesium chips and 50 mL of anhydrous tetrahydrofuran were added in sequence. The anhydrous tetrahydrofuran solution of 5-bromo-2-chloro-4'-fluorodiphenylmethane (51.5 g, 171.9 mmol of 5-bromo-2-chloro-4'-fluorodiphenylmethane, 100 mL of anhydrous tetrahydrofuran) was transferred to a dropping funnel. About 5 mL was first added dropwise to initiate the reaction. Then the temperature was lowered to 0-5°C and the remaining bromide solution was added dropwise. The addition was slowly dropped for 2 hours. After the dropwise addition was completed, the temperature was raised to 30-35°C and the reaction was kept warm for 2 hours to obtain a 4-chloro-3-(4-fluorobenzyl)phenylmagnesium bromide solution for use.

[0111] Step 2: Preparation of 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-glucopyranose

[0112]

[0113] To the 4-chloro-3-(4-fluorobenzyl)phenylmagnesium bromide solution prepared in step 1, add 300 mL of anhydrous toluene, cool to -30 ° C, control the temperature ≤ -20 ° C, slowly add TMS-GDL toluene solution (TMS-GDL: 95 g, 203.4 mmol, toluene: 350 mL), add dropwise for about 1 hour, control the temperature at -30 to -20 ° C, keep the reaction for 2 hours, add 200 g of acetic acid aqueous solution with a mass fraction of 7.5%, heat to 20 to 30 ° C, keep the reaction for 0.5 hours, remove the low boiling point solvent by reduced pressure distillation, separate the liquids, and remove the solvent from the organic phase by reduced pressure distillation to obtain a light yellow oily 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-pyranose concentrate.

[0114] Step 3: Preparation of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-glucopyranoside

[0115]

[0116] The 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-pyranose glucose concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 2.4 g of hydrochloric acid was added, and the mixture was stirred at room temperature for 18 hours. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.6, and the mixture was distilled under reduced pressure. The mixture was crystallized from tetrahydrofuran-heptane to obtain 63.2 g of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranose glucoside, with a yield (total yield of 3 steps) of 89.0% and a purity of 98.7%.

[0117] 1 HNMR (CDCl 3 ,400MHz)δ7.35(s,1H,4-chlorophenyl-5-CH),7.25(m,1H,4-chlorophenyl-2-CH),7.21(m,1H,4-chlorop henyl-6-CH),7.02(d,2H,4-fluorophenyl-2,6-CH),6.67(d,2H,4-fluorophenyl-3,5-CH),5.29(s,1H,α- D-glucopyranoside-4-OH),5.19(s,1H,α-D-glucopyranoside-2-OH),4.77(s,1H,α-D-glucopyranoside- 3-OH),4.31(d,1H,α-D-glucopyranoside-2-CH),3.89(m,1H,α-D-glucopyranoside-6-OH),3.79(m,2H,CH 2 ),3.51(dd,1H,α-D-glucopyranoside-3-CH),3.18(m,1H,α-D-glucopyranoside-4-CH),3.17(m,1H,α-D-glucopyranoside-5-CH),3.15(m,2H,α-D-glucopyranoside-6-CH 2 ),2.84(s,3H,α-D-glucopyranoside-1-OCH 3 ).

[0118] 13 CNMR (CDCl 3 ,100MHz)δ155.7(1C,4-fluorophenyl-C-4),138.4(1C,4-chlorobenzene-C-3),136.8(1C,4-chlorophenyl-C-1),134.2(1C,4-fluorophenyl-C -1),131.9(2C,4-chlorophenyl-C-2,4),130.1(1C,4-chlorophenyl-C-5),129.8(2C,4-fluorophenyl-C-2,6),129.2(1C,4-chlorophenyl-C-6 ),126.9(1C,α-D-glucopyranoside-C-1),115.3(2C,4-fluorophenyl-C-3,5),101.0(1C,α-D-glucopyranoside-C-5),74.6(1C,α-D-glucopyra noside-C-3),72.7(1C,α-D-glucopyranoside-C-4),70.0(1C,α-D-glucopyranoside-C-2),61.7(1C,α-D-glucopyranoside-C-6),49.1(1C,-OCH 3 ),38.4(1C,-CH 2 ).

[0119] Example 6: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside

[0120]

[0121] 59.3 g (143.6 mmol) of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranoglucoside prepared in Example 5 was added into a 1000 mL four-necked bottle, 500 g of tetrahydrofuran was added and stirred to dissolve, 15.2 g (172.5 mmol) of s-3-hydroxytetrahydrofuran was added, the temperature was lowered to 0-5° C., 27 g (240.6 mmol) of potassium tert-butoxide was added in batches, the temperature was raised to 10-15° C., the reaction was kept warm for 2 h, 100 g of ice brine was added to quench the reaction, the liquid was separated, the organic phase was evaporated to dryness, and tetrahydrofuran-heptane crystallization was used to obtain 64.8 g of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside, the yield was 93.8%, and the purity was 98.5%.

[0122] Example 7: Preparation of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranoglucoside

[0123] Step 1: Preparation of 4-chloro-3-(4-fluorobenzyl)phenylmagnesium iodide

[0124]

[0125] The 2L four-necked bottle was replaced with nitrogen three times. Under the protection of nitrogen flow, 5.0 g (205.7 mmol) of magnesium chips, 50 mL of anhydrous tetrahydrofuran, 0.05 g of iodine and 1 g of 5-bromo-2-chloro-4'-fluorodiphenylmethane were added in sequence. The temperature was raised to 55°C to initiate the reaction. The temperature was lowered to 0-5°C, and a solution of 5-bromo-2-chloro-4'-fluorodiphenylmethane in anhydrous tetrahydrofuran (50.5 g of 5-bromo-2-chloro-4'-fluorodiphenylmethane and 100 mL of anhydrous tetrahydrofuran) was slowly added dropwise for 2 hours. After the addition was completed, the temperature was raised to 30-35°C and the reaction was kept warm for 2 hours to obtain a 4-chloro-3-(4-fluorobenzyl)phenylmagnesium iodide solution for use.

[0126] Step 2: Preparation of 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-glucopyranose

[0127]

[0128] To the 4-chloro-3-(4-fluorobenzyl)phenylmagnesium iodide solution prepared in step 1, add 300 mL of toluene, cool to -30 ° C, control the temperature ≤ -20 ° C, slowly add TMS-GDL toluene solution (TMS-GDL: 95 g, 203.4 mmol, toluene: 350 mL), add dropwise for about 1 hour, control the temperature at -30 to -20 ° C, keep the reaction for 2 hours, add 200 g of acetic acid aqueous solution with a mass fraction of 7.5%, raise the temperature to 20 to 30 ° C, keep the reaction for 0.5 hours, remove the low boiling point solvent by reduced pressure distillation, separate the liquids, and remove the solvent from the organic phase by reduced pressure distillation to obtain a light yellow oily 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-pyranose concentrate.

[0129] Step 3: Preparation of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-glucopyranoside

[0130]

[0131] The 1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-D-pyranose glucose concentrate prepared in step 2 was added into a 500 mL four-necked bottle, 300 g of methanol was added and stirred to dissolve, 2.4 g of hydrochloric acid was added, and the mixture was stirred at room temperature for 18 hours. A saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7.6, and the mixture was distilled under reduced pressure to obtain 62.7 g of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranose glucose sideroside crystallized from tetrahydrofuran-heptane, with a yield (total yield of 3 steps) of 88.3% and a purity of 98.9%.

[0132] Example 8: Preparation of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside

[0133]

[0134] 59.3 g (143.6 mmol) of methyl-1-C-[4-chloro-3-[(4-fluorophenyl)methyl]phenyl]-α-D-pyranoglucoside prepared in Example 7 was added into a 1000 mL four-necked bottle, 500 g of tetrahydrofuran was added and stirred to dissolve, 15.2 g (172.5 mmol) of s-3-hydroxytetrahydrofuran was added, the temperature was lowered to 0-5° C., 27 g (240.6 mmol) of potassium tert-butoxide was added in batches, the temperature was raised to 10-15° C., the reaction was kept warm for 2 h, 100 g of ice brine was added to quench the reaction, the liquid was separated, the organic phase was evaporated to dryness, and tetrahydrofuran-heptane crystallization was used to obtain 65.2 g of methyl-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-α-D-pyranoglucoside, the yield was 94.4%, and the purity was 98.8%.

[0135] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a linalool intermediate compound, characterized in that: The structure of the intermediate compound of the levofloxacin class is shown in Compound I: The preparation method of the intermediate compound of the linaloxone class comprises the following steps: Step 1: Metal magnesium and compound IV are subjected to a Grignard reaction to obtain compound III. The synthesis route is as follows: Step 2, compound III and compound V are subjected to nucleophilic addition and deprotection reaction to obtain compound II. The synthetic route is as follows: Step 3, subjecting compound II to a methylation reaction to obtain compound I. The synthetic route is as follows: In the compounds I-IV, R is selected from fluorine atoms, In the compounds III and IV, X is selected from chlorine, bromine or iodine; In the compound V, R 1 is a protecting group for the hydroxyl group, selected from one of trimethylsilyl, benzyl and acyl.

2. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In the step 1, the temperature of the Grignard reaction is 0 to 55° C.; in the step 2, the temperature of the nucleophilic addition and deprotection reaction is −30 to 30° C.; in the step 3, the temperature of the methylation reaction is room temperature.

3. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In the compounds III and IV, X is selected from bromine or iodine; in the compound V, R 1 Selected from trimethylsilyl.

4. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In step 1 and step 2, the Grignard reaction and the nucleophilic addition reaction adopt anhydrous solvent, and the anhydrous solvent is selected from one or more of anhydrous ether, anhydrous ethylene glycol dimethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous toluene, anhydrous xylene, anhydrous hexane, anhydrous heptane or anhydrous tetrahydrofuran.

5. The method for preparing the intermediate compound of levitra according to claim 4, characterized in that: The anhydrous solvent in the Grignard reaction is selected from anhydrous ether or anhydrous tetrahydrofuran, preferably anhydrous tetrahydrofuran; the anhydrous solvent in the nucleophilic addition reaction is selected from anhydrous ether, anhydrous tetrahydrofuran, a mixture of anhydrous ether and anhydrous toluene, and a mixture of anhydrous tetrahydrofuran and anhydrous toluene, preferably a mixture of anhydrous tetrahydrofuran and anhydrous toluene.

6. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In step 1, the molar ratio of compound IV to metallic magnesium is 1:1-2, preferably 1:1-1.

5.

7. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In step 2, the molar ratio of compound III to compound V is 1:1 to 1.5, preferably 1:1 to 1.

2.

8. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In step 2, the deprotection reaction adopts a dilute acid, and the dilute acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, formic acid, acetic acid, oxalic acid or citric acid, preferably acetic acid or citric acid, more preferably acetic acid.

9. The method for preparing the intermediate compound of levitra according to claim 1, characterized in that: In step 3, hydrochloric acid and methanol are used for the methylation reaction.

10. The method for preparing a levitra intermediate compound according to claim 14, characterized in that: In the step 3, the molar ratio of compound II to hydrochloric acid is 1:0.1-10, preferably 1:0.1-2.

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