An efficient preparation method for empagliflozin intermediate

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology and specifically relates to a method for preparing an empagliflozin intermediate compound. The method uses 2-chloro-5-iodobenzyl bromide and (S)-3-(4-bromophenoxy)tetrahydrofuran as starting materials, reacting them under the catalysis of magnesium and 2,2,6,6-tetramethylpiperidinyl oxide to produce the empagliflozin intermediate compound (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran. This process eliminates the need for n-butyl lithium, has a short synthetic route, is simple to operate, and is more suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a method for efficiently preparing an empagliflozin intermediate. Background Art

[0002] Empagliflozin, chemically known as (2S,3R,4R,5S,6R)-2-[3-[4-[(S)-tetrahydrofuran-3-yloxy]benzyl]-4-chlorophenyl]-6-hydroxymethylepoxyhexane-3,4,5-triol, was jointly developed by Boehringer Ingelheim and Eli Lilly and Company and was first approved for marketing by the European Medicines Agency (EMA) in May 2014. It effectively lowers blood sugar, improves insulin sensitivity and pancreatic beta cell function through a mechanism independent of insulin secretion and insulin action, and is the first SGLT2 hypoglycemic drug to reduce the risk of cardiovascular disease, heart disease, and stroke. It has a molecular weight of 450.91, CAS registration number: 864070-44-0, and the structural formula is as follows:

[0003]

[0004] The retrosynthetic analysis of empagliflozin shows that it is mainly composed of sugar groups and side chains. The following methods have been reported for the synthesis of side chains:

[0005] Method 1: Chinese patent application CN105399735 uses 5-iodo-2-chlorobenzoic acid 1 as a raw material, which reacts with oxalyl chloride in the presence of DMF to obtain compound 2. Compound 2 undergoes Friedel-Crafts acylation with fluorinated benzene in the presence of Lewis acid aluminum chloride to obtain compound 4. Compound 4 undergoes SN2 nucleophilic substitution reaction with (S)-3-hydroxytetrahydrofuran in the presence of strong base potassium tert-butoxide to obtain compound 6. Compound 6 is reduced with sodium borohydride-aluminum chloride system to obtain side chain compound I. The synthetic route is as follows:

[0006]

[0007] This route has long steps and low yield, and uses oxalyl chloride, which is highly toxic, and is not suitable for large-scale industrial production.

[0008] Method 2: Chinese patent CN108178751 reports that 4-hydroxybenzyl chloride is used as the starting material, which is reacted with methanesulfonyl chloride and (S)-3-hydroxytetrahydrofuran in sequence to obtain compound 8, which is then reacted with 4-iodoaniline to obtain compound 10. Finally, after diazotization, the compound is reacted with cuprous chloride to obtain (S)-3-(4-(5-iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran:

[0009]

[0010] Although this route uses cheap starting materials, the premature introduction of (S)-3-hydroxytetrahydrofuran causes it to be easily racemized in subsequent reactions. In addition, the reaction involves diazotization, which is difficult to operate and the post-processing is cumbersome.

[0011] Method 3: Chinese patent application CN110683998 uses p-methoxybenzyl chloride and p-iodoaniline as raw materials, and undergoes a substitution reaction under Lewis acid catalysis to obtain the compound 4-iodo-2-(4-methoxybenzyl)aniline shown as compound 12. Compound 12 is subjected to diazotization and Sandmeyer reaction to obtain compound 13, namely 1-chloro-4-iodo-2-(4-methoxybenzyl)benzene. Compound 13 is subjected to boron tribromide demethylation to obtain compound 14, namely 4-(2-chloro-5-iodophenyl)benzene. 4-(2-chloro-5-iodophenyl)benzene is subjected to a condensation reaction with (S)-3-p-toluenesulfonyloxytetrahydrofuran to obtain the target product:

[0012]

[0013] Although this method places the (S)-3-hydroxytetrahydrofuran at the end of the process, the process uses reagents such as diazotization reaction and boron tribromide, which is not conducive to industrial production.

[0014] In view of the above problems in the current preparation of empagliflozin side chain (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran, it is currently necessary to find a route suitable for industrial production with mild reaction conditions, simple operation process, high product yield, high purity and low production cost. Summary of the Invention

[0015] In order to overcome the defects of the existing technology and solve the problems that the reaction for preparing the side chain of empagliflozin (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran requires the hazardous chemical n-butyl lithium, the reaction steps are long, and the yield is low, and to obtain a process more suitable for industrial production, the present invention provides a new method for preparing the empagliflozin intermediate compound (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran. The target product prepared by this method has high purity and yield, and is characterized by mild reaction conditions, simple operation process, and lower production cost.

[0016] The specific technical contents of the present invention are as follows:

[0017] A method for preparing the empagliflozin intermediate compound (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran, the specific process of which is as follows:

[0018]

[0019] An efficient preparation method of an empagliflozin intermediate compound specifically comprises the following steps:

[0020] Step 1: Under inert gas protection, compound SM-1 is added to a reaction flask, magnesium and organic solvent A are added, and the reaction is carried out at low temperature until the reaction is completed, and reaction solution A is obtained for later use; SM-2 is added to a reaction flask, magnesium and organic solvent A are added, and the reaction is carried out at low temperature until the reaction is completed, and reaction solution B is obtained for later use;

[0021] Step 2: Add 2,2,6,6-tetramethylpiperidinyl oxide to organic solvent B, add the reaction solution A and reaction solution B prepared above, control the temperature and reflux until the reaction is completed, and post-process the reaction to obtain compound I.

[0022] Preferably, the organic solvent A in step 1 is selected from anhydrous ether, anhydrous tetrahydrofuran, or a combination thereof.

[0023] Preferably, the reaction temperature in step 1 is -30°C to -10°C.

[0024] Preferably, the organic solvent B in step 2 is selected from anhydrous tetrahydrofuran, acetonitrile and toluene.

[0025] Preferably, the molar ratio of the compound SM-1, compound SM-2, magnesium chips, and 2,2,6,6-tetramethylpiperidinyl oxide is 1.0:1.0:1.0~1.8:1.8~2.8, with 1.0:1.0:1.1:2.0 being particularly preferred.

[0026] Preferably, the molar ratio of the compound SM-2 to magnesium is 1.0:1.0 to 1.8, with 1.0:1.1 being particularly preferred.

[0027] In a preferred embodiment, after the reaction is completed, post-treatment is required. The specific steps are as follows: after the reaction is completed, diluting with a saturated aqueous solution of ammonium chloride, separating the organic phase, extracting the aqueous phase with methyl tert-butyl ether, combining the organic layers, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, and distilling the filtrate to remove the solvent under reduced pressure. The crude product is recrystallized from toluene / isopropanol to obtain Compound I.

[0028] Compared with the prior art, the technical effects achieved by the present invention are:

[0029] 1. The present invention provides a new method for preparing the side chain compound of empagliflozin (S)-3-(4-(2-chloro-5-iodophenyl)phenoxy)tetrahydrofuran, which uses 2,2,6,6-tetramethylpiperidinyl oxide as a catalyst and has a high reaction yield;

[0030] 2. This process can solve the use of n-butyl lithium. The entire synthesis route is short, the operation is simple, and it is more suitable for large-scale industrial production. DETAILED DESCRIPTION

[0031] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0032] The structure of the compound obtained by the present invention is confirmed:

[0033]

[0034] HPLC peak area normalization method:

[0035] Chromatographic column: YMC-Triart C 18 Column (4.6 mm × 250 mm, 5 μm);

[0036] Mobile phase: acetonitrile: water (85:15);

[0037] Column temperature: 40°C;

[0038] Detection wavelength: 220nm;

[0039] Flow rate: 1.0 ml / min;

[0040] Injection volume: 10 μl;

[0041] Retention time: 12.5min.

[0042] ESI-HRMS: m / z = 415.6672 [M+H] + ,mp 63.4~64.8℃, 1 H-NMR(400MHz,DMSO-d6)δ:7.65(s,1H),7.61(d,1H),7.18(d,1H),7.09(d,2H),6.89(d,2H),4.25(d ,1H),4.05(m,1H),4.00(d,1H),3.99(s,2H),3.80(t,1H),3.70(t,1H),2.36(dt,1H),2.11(dt,1H); 13 C-NMR (100MHz, DMSO-d6) δ: 154.9, 145.0, 140.5, 136.5, 133.1, 132.4, 130.9, 128.8, 128.9, 115.0, 114.9, 92.9, 80.8, 79.6, 67.5, 35.3, 32.2.

[0043] Preparation of Compound I

[0044] Example 1

[0045] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous ether (100 mL) were added to a two-necked flask, and the mixture was reacted at -20°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous ether (100 mL) were added, and the mixture was reacted at -20°C for 4 hours under argon protection to obtain reaction solution B.

[0046] 2,2,6,6-tetramethylpiperidinyl oxide (64.66 g, 0.41 mol) and dry tetrahydrofuran (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 97.2% and an HPLC purity of 99.89%.

[0047] Example 2

[0048] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (4.86 g, 0.2 mol) and anhydrous ether (100 mL) were added to a two-necked flask, and the mixture was reacted at -20°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (4.86 g, 0.2 mol) and anhydrous ether (100 mL) were added, and the mixture was reacted at -20°C for 4 hours under argon protection to obtain reaction solution B.

[0049] 2,2,6,6-tetramethylpiperidinyl oxide (64.66 g, 0.41 mol) and dry acetonitrile (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 94.2% and an HPLC purity of 99.60%.

[0050] Example 3

[0051] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (8.75 g, 0.36 mol) and anhydrous ether (100 mL) were added to a two-necked flask, and the mixture was reacted at -10°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (8.75 g, 0.36 mol) and anhydrous ether (100 mL) were added, and the mixture was reacted at -10°C for 4 hours under argon protection to obtain reaction solution B.

[0052] 2,2,6,6-tetramethylpiperidinyl oxide (64.66 g, 0.41 mol) and dry toluene (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 94.8% and an HPLC purity of 99.48%.

[0053] Example 4

[0054] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous tetrahydrofuran (100 mL) were added to a two-necked flask, and the mixture was reacted at -20°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous tetrahydrofuran (100 mL) were added, and the mixture was reacted at -20°C for 4 hours under argon protection to obtain reaction solution B.

[0055] 2,2,6,6-tetramethylpiperidinyl oxide (56.25 g, 0.36 mol) and dry tetrahydrofuran (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 94.3% and an HPLC purity of 99.51%.

[0056] Example 5

[0057] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous tetrahydrofuran (100 mL) were added to a two-necked flask, and the mixture was reacted at -30°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous ether (100 mL) were added, and the mixture was reacted at -30°C for 4 hours under argon protection to obtain reaction solution B.

[0058] 2,2,6,6-tetramethylpiperidinyl oxide (87.5 g, 0.56 mol) and dry tetrahydrofuran (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, which was repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 94.3% and an HPLC purity of 99.51%.

[0059] Example 6

[0060] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous tetrahydrofuran (100 mL) were added to a two-necked flask, and the mixture was reacted at -35°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (5.34 g, 0.22 mol) and anhydrous ether (100 mL) were added, and the mixture was reacted at -35°C for 4 hours under argon protection to obtain reaction solution B.

[0061] 2,2,6,6-tetramethylpiperidinyl oxide (46.88 g, 0.3 mol) and dry tetrahydrofuran (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 87.3% and an HPLC purity of 98.89%.

[0062] Example 7

[0063] Compound SM-1 (66.27 g, 0.20 mol), magnesium turnings (9.72 g, 0.4 mol) and anhydrous tetrahydrofuran (100 mL) were added to a two-necked flask and reacted at -5°C for 3 hours under argon protection to obtain reaction solution A. In another two-necked flask, compound SM-2 (48.62 g, 0.20 mol), magnesium turnings (9.72 g, 0.4 mol) and anhydrous ether (100 mL) were added and reacted at -5°C for 4 hours under argon protection to obtain reaction solution B.

[0064] 2,2,6,6-tetramethylpiperidinyl oxide (93.76 g, 0.6 mol) and dry tetrahydrofuran (800 mL) were added to a two-necked flask, stirred under reflux to dissolve, and the above reaction solution A and reaction solution B were slowly added dropwise in sequence. After the addition was complete, the reaction flask was filled with oxygen and refluxed for 30 minutes, and repeated 6 times. After the reaction was completed, it was diluted with a saturated aqueous solution of ammonium chloride (1200 mL), the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (1000 mL × 3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was recrystallized from toluene / isopropanol, compound I, with a yield of 84.8% and an HPLC purity of 98.21%.

Claims

1. An efficient preparation method of an empagliflozin intermediate, characterized in that: The preparation method comprises the following steps: Step 1: Under inert gas protection, compound SM-1 is added to a reaction flask, magnesium and organic solvent A are added, and the reaction is carried out at low temperature until the reaction is completed, and reaction solution A is obtained for later use; SM-2 is added to a reaction flask, magnesium and organic solvent A are added, and the reaction is carried out at low temperature until the reaction is completed, and reaction solution B is obtained for later use; Step 2: Add 2,2,6,6-tetramethylpiperidinyl oxide to organic solvent B, add the reaction solution A and reaction solution B prepared above, fill the reaction bottle with oxygen and reflux for 30 minutes, repeat 6 times, and after the reaction is completed, the reaction is post-treated to obtain compound I. The low temperature reaction temperature of step 1 is -30°C to -10°C; The synthetic route is as follows: 。 2. The preparation method according to claim 1, characterized in that The organic solvent A described in step 1 is selected from one of anhydrous ether and anhydrous tetrahydrofuran or a combination thereof.

3. The preparation method according to claim 1, wherein The organic solvent B in step 2 is selected from anhydrous tetrahydrofuran, acetonitrile and toluene.

4. The preparation method according to claim 1, characterized in that The molar ratio of the compound SM-1, the compound SM-2, magnesium chips, and 2,2,6,6-tetramethylpiperidinyl oxide is 1.0:1.0:1.0~1.8:1.8~2.8.

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