Process for the preparation of empagliflozin intermediates

Abstract

The present application relates to a kind of asymmetric catalytic hydrogenation synthesis new method of (S)‑3‑(4‑(5‑bromo / iodine‑2 chlorobenzyl) phenoxy) tetrahydrofuran in engletin intermediate.This method is prepared by acylation, reduction from simple raw material, and formula a-1 compound is obtained.In which formula a-1 compound and formula a compound, through asymmetric catalytic hydrogenation process, and intramolecular dehydration ring-closing reaction synthesis (S)‑3‑(4‑(5‑bromo / iodine‑2 chlorobenzyl) phenoxy) tetrahydrofuran in engletin intermediate.The raw material of this synthesis method is easy to obtain, simple operation, suitable for industrial amplification.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and particularly relates to a preparation method of empagliflozin and intermediates thereof. BACKGROUND

[0002] Empagliflozin is a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor jointly developed by Boehringer Ingelheim and Lilly, which has been clinically used for the treatment of type 2 diabetes and has been marketed in the United States, Europe, Japan, China and other countries. Empagliflozin is a chiral compound containing (S)-3-aryloxy-substituted tetrahydrofuran and -D-glucitol structural fragments. The synthesis of empagliflozin is mainly completed by the nucleophilic addition reaction of (S)-3-(4-(5-bromo / iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran as a key intermediate to glucoside lactone (J. Label Compd. Radiopharm. 2014, 57, 687-694; Org. Lett. 2014, 16, 4090-4093) or the palladium-catalyzed coupling method (Org. Lett. 2018, 20, 1936-1940). Among them, the introduction of the chiral tetrahydrofuran fragment in the key intermediate (S)-3-(4-(5-bromo / iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran is also mainly synthesized by using (S)- or (R)-3-hydroxytetrahydrofuran as a chiral raw material through Mitsunobu nucleophilic substitution reaction, etc., which has the disadvantages of poor atom economy, etc. In addition, there are also the disadvantages of high cost of raw materials, complicated post-treatment and poor environmental friendliness. However, most of the current domestic and foreign patents and literatures use such traditional synthesis methods for synthesis.

[0003] In addition, asymmetric catalysis is the most effective method for synthesizing chiral compounds, and in particular, asymmetric catalytic hydrogenation with the characteristics of good atom economy, green, efficient and environmentally friendly has been widely used in the industrial production of chiral drugs. However, due to the lack of corresponding asymmetric synthesis methods and technologies such as asymmetric catalytic hydrogenation, there is still no report on the asymmetric synthesis of the key chiral intermediate of empagliflozin. Therefore, in view of the shortcomings and deficiencies of the existing methods and technologies for synthesizing the key chiral intermediate of empagliflozin, the present application develops and provides a new method for asymmetric synthesis of the key chiral intermediate of empagliflozin by asymmetric catalytic hydrogenation of α-aryloxy-substituted γ-lactone as a key step. Starting from simple raw materials, the asymmetric synthesis of (S)-3-(4-(5-bromo / iodo-2-chlorobenzyl)phenoxy)tetrahydrofuran can be completed by only 4-step reactions including asymmetric catalytic hydrogenation. The new synthesis method is simple to operate, avoids the Mitsunobu nucleophilic substitution reaction with poor atom economy, and has the advantages of green, efficient, environmentally friendly, etc. SUMMARY

[0004] The present application provides an intermediate of empagliflozin and a preparation process thereof, which is simple in operation, low in cost, good in atom economy and suitable for industrial production.

[0005] Firstly, the present application provides a compound of general structure of formula A-1 or formula A-2,

[0006]

[0007] wherein X is halogen, preferably bromine or iodine, R1 and R2 are the same and are hydroxyl or combined into a lactone ring, and R3 is hydrogen or hydroxyl.

[0008] Further, the present application provides a compound of the following structure,

[0009]

[0010] wherein X is halogen, preferably bromine or iodine.

[0011] The present application provides a preparation method of the compound of formula a, which is prepared from compound 2 and compound 3 through a Friedel-Crafts acylation reaction.

[0012] The Friedel-Crafts acylation reaction route is as follows:

[0013]

[0014] wherein X is halogen, preferably bromine or iodine.

[0015] In the Friedel-Crafts acylation reaction, the reaction temperature ranges from 50 to 150°C, and the catalyst is polyphosphoric acid (PPA) or the like.

[0016] The present application provides a preparation method of the compound of formula a-1, which is prepared from the compound of formula a through a reduction reaction under the action of a reducing agent,

[0017]

[0018] wherein X is halogen, preferably bromine or iodine.

[0019] In the reduction reaction, the reducing agent can be sodium borohydride, potassium borohydride, triethylsilane, 1,1,3,3-tetramethyldisiloxane or tetramethyldisilazane, etc.; a protonic acid or an acid such as aluminum chloride, trifluoroacetic acid, etc. needs to be added; the reaction solvent is one of dichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent of several thereof; and the reaction temperature ranges from -10 to 85°C.

[0020] The present application provides a preparation method of the compound of formula b, which is prepared from the compound of formula a through an asymmetric catalytic hydrogenation reaction,

[0021]

[0022] wherein X is halogen, preferably bromine or iodine.

[0023] The present application provides a method for preparing compound of formula c, which is prepared from compound of formula b by debenzylating the hydroxyl group, or prepared from compound of formula a-1 by asymmetric catalytic hydrogenation,

[0024]

[0025]

[0026] wherein X is halogen, preferably bromine or iodine.

[0027] In the above asymmetric catalytic hydrogenation, the catalyst is a chiral catalyst, and the general structure is compound of formula 5 or compound of formula 6.

[0028]

[0029] wherein n in compound of formula 5 is 0-4; R 1 selected from C1-C10 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl or benzyl, the substituents on the phenyl are C1-C10 alkyl, alkoxy, and the number of substituents is 1-5, and the heteroaryl is furanyl, thienyl or pyridyl;

[0030] R 1 , R 2 selected from C1-C10 alkyl, phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl, heteroaryl or benzyl, the substituents on the phenyl are C1-C10 alkyl, alkoxy, and the number of substituents is 1-5, and the heteroaryl is furanyl, thienyl or pyridyl; wherein R 1 , R 2 may be the same or different;

[0031] Typical representatives of compounds of formula 5 and 6 are as follows:

[0032]

[0033] In the asymmetric hydrogenation, the molar ratio of the chiral catalyst to compound a or a-1 is 100:1-50000:1; and the concentration of compound a or a-1 is 0.001-10.0 M;

[0034] The asymmetric hydrogenation reaction is carried out in the presence of a base. The base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, tributylamine or N-methylmorpholine; the concentration of the base is 0.005M-1.0M. The hydrogen pressure is 0.1-100atm; the reaction temperature ranges from 0-80℃; the organic solvent is one of methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, toluene, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent of several thereof.

[0035] The present application provides a preparation method of the intermediate of empagliflozin of formula d, which is prepared from the compound of formula c by dehydration and ring closure reaction,

[0036]

[0037] wherein X is halogen, preferably bromine or iodine;

[0038] The dehydrating agent used is p-toluenesulfonic acid, p-toluenesulfonyl chloride, benzene sulfonic acid, sulfuric acid, methylsulfonyl chloride; the reaction solvent is one of dichloromethane, acetonitrile, toluene, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide or a mixed solvent of several thereof; the reaction temperature is 20-150℃.

[0039] The synthesis of the intermediate of empagliflozin provided by the present application is synthesized by asymmetric catalytic hydrogenation as a key step, which has the advantages of simple operation, good atom economy and high yield, and provides a new green, efficient and environmentally friendly synthesis method for the asymmetric synthesis of the key chiral intermediate of the chiral drug empagliflozin. DETAILED DESCRIPTION

[0040] In order to further understand the present application, the preparation method of the intermediate of empagliflozin provided by the present application is described in detail below in combination with examples. It should be understood that these example descriptions are only for further detailed description of the features of the present application, and are not a limitation on the scope of the present application or the scope of the claims of the present application.

[0041] Example 1:

[0042]

[0043] A 250 mL two-necked flask was charged with polyphosphoric acid (37.6 g) and heated to 60 °C. Then 5-bromo-2-chlorobenzoic acid (4.72 g, 20 mmol) and compound 2 (3.56 g, 20 mmol) were added successively. The reaction mixture was heated to 100 °C for 4 h. Then it was cooled to 50 °C and water (100 mL) was added. Stirring was continued for 1 h and dichloromethane (50 mL) was added. After stirring for 1 h, the organic phase was separated and the aqueous phase was extracted with dichloromethane (30 x 3 mL). The organic phases were combined and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give a crude product which was purified by column chromatography (petroleum ether / ethyl acetate (4:1-2:1)) to give compound a as a yellow solid 4.5 g, 58% yield. Melting point: 102-105 °C. 1 H NMR (400 MHz, CDC13) δ 7.86 - 7.74 (m, 2H), 7.55 (dd, J = 8.6, 2.4 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.16 - 7.01 (m, 2H), 5.08 (t, J = 8.0 Hz, 1H), 4.61 - 4.50 (m, 1H), 4.45 - 4.35 (m, 1H), 2.84 - 2.71 (m, 1H), 2.58 - 2.44 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 192.0, 172.6, 161.7, 140.3, 133.9, 132.5, 131.6, 131.5, 130.2, 130.1, 120.6, 115.6, 72.1, 65.4, 29.7. HRMS (ESI) Calcd for C 17 H 13 BrClO4([M+H] + ): 394.9680; Found: 394.9681.

[0044] Example 2:

[0045]

[0046] Into a 250 mL two-necked flask, AlCl3(2.4 g, 18.2 mmol) was added, followed by compound a (3.6 g, 9.1 mmol). The flask was purged with argon, and toluene (100 mL) was added. The system was cooled to 0 °C, and 1,1,3,3-tetramethyldisiloxane (2.43 g, 18.2 mmol) was added slowly, followed by stirring at room temperature for 1 h. After the reaction was completed, the system was cooled to 0 °C, and ice water was added for quenching. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4:1) to give 2.5 g of compound a-1 as a white solid in 73% yield. Melting point: 93-94 °C. 1 H NMR (400 MHz, CDC13) δ 7.29 (dd, J = 8.4, 2.4 Hz, 1H), 7.26 - 7.21 (m, 2H), 7.15 - 7.08 (m, 2H), 7.01 - 6.95 (m, 2H), 4.93 (t, J = 7.8 Hz, 1H), 4.56 - 4.49 (m, 1H), 4.40 - 4.32 (m, 1H), 4.00 (s, 2H), 2.75 - 2.67 (m, 1H), 2.52 - 2.41 (m, 1H). 13 C NMR (101 MHz, CDC13) δ 173.5, 156.0, 140.9, 133.6, 133.1, 132.5, 130.9, 130.7, 130.1, 120.5, 116.1, 72.6, 65.3, 38.2, 29.9. HRMS (ESI) Calcd for C 17 H 19 BrClO3Na ([M + Na] + ): 402.9707; Found: 402.9710.

[0047] Example 3:

[0048]

[0049] Into the inner tube of a hydrogenation reactor, compound a-1 (1.14 g, 3.0 mmol), chiral spiro oxazoline catalyst 6c (3.0 mg, 3.0 μmol), potassium tert-butoxide (336 mg, 3.0 mmol), and 20 mL of n-propanol were sequentially added under argon protection. The reactor was sealed, and the gas in the reactor was rapidly replaced with hydrogen three times. The hydrogen pressure was adjusted to 10 atm, and the system was stirred at room temperature until the hydrogen pressure no longer decreased. After the reaction was completed, the hydrogen in the reactor was slowly released, and the solvent was removed by rotary evaporation to give the crude product. Column chromatography gave 932 mg of compound c as an oily liquid in 80% yield with an ee value of 93%. (c 0.5, EtOH).1 H NMR (400 MHz, CDC13) δ 7.31 - 7.25 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.59 - 4.52 (m, 1H), 3.99 (s, 2H), 3.89 - 3.73 (m, 4H), 2.38 - 1.89 (m, 4H). 13 CNMR (101 MHz, CDC13) δ 156.5, 141.1, 133.6, 133.1, 131.5, 130.9, 130.6, 130.1, 120.5, 116.3, 76.4, 64.2, 59.0, 38.2, 33.8. HRMS (ESI) Calcd for C 17 H 19 BrClO3([M+H] + ): 385.0201; Found: 385.0199. HPLC conditions: Chiralcel IC-3 column (25 cm x 0.46 cm ID); n-hexane / 2-propanol = 90:10; temp, rt; flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 12.0 min (minor); t R (S) = 13.7 min (major).

[0050] Example 4:

[0051]

[0052] Into a 10 mL vial, was added compound c (384 mg, 1.0 mmol), anhydrous p-toluenesulfonic acid (86 mg, 0.5 mmol) successively. Dry toluene (2 mL) was added under argon protection, and the vial was tightly capped. The reaction was carried out at 110 °C for 24 h. Cooled to room temperature, water was added, and ethyl acetate was extracted three times (2 mL x 3). Dried over anhydrous magnesium sulfate, suction filtered, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5:1) to give 329 mg of colorless liquid compound d with a yield of 90%. (c 0.5, CHCl3). 1H NMR (400MHz, CDCl3) δ7.31–7.20(m,3H),7.09(d,J=8.6Hz,2H),6.80(d,J=8.8Hz, 2H),4.93–4.86(m,1H),4.02–3.94(m,5H),3.93–3.86(m,1H),2.25–2.10(m,2H). 13 C NMR(101MHz, CDCl3)δ156.1,141.2,133.6,133.1,130.9,130.6,130.1,120.5,115.5,77.3,73.2,67.2,38.2,33.0.HRMS(ESI)Calcd for C 17 H 20 BrClNO2([M+NH4] + ):384.0380; Found:384.0368.

[0053] Example 5:

[0054]

[0055] Weigh 1.0 mg of chiral catalyst and 2.6 mg of ligand into the glove box, add them to the inner tube of the hydrogenation reactor, seal the tube with sealing film, and remove it from the glove box. Quickly place it into the hydrogenation reactor, seal the reactor, and add 3 mL of [unspecified substance]. n After purging PrOH three times with nitrogen, the system was stirred at room temperature for 30 min, then purged three times with hydrogen, and purged with 20 atm of hydrogen. The system was then stirred at room temperature for another 30 min. Separately, 1.19 g of compound a and 336 mg of PrOH were weighed from the inner tube of the hydrogenation process in a glove box. t Okay, seal the glove box with sealing film and quickly place it inside the hydrogenation reactor, then seal the reactor. Replace the hydrogenation reactor with a nitrogen atmosphere, and add 18 mL of nitrogen gas to the system while stirring. nPrOH, then 3 mL of a solution of chiral catalyst 6c was added, hydrogen was replaced three times, 10 atm of hydrogen was charged, the system was stirred at room temperature for 12 h, and the hydrogen pressure did not decrease significantly. The pressure was released, the reactor was opened, and the reaction solution was slowly added to a semi-saturated ammonium chloride solution at 0 °C for quenching. DCM was used for extraction three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. This was the crude compound of formula b. The crude compound of formula b and 0.72 mL of Et3SiH were dissolved in 21 mL of DCM, the system was cooled with an ice bath, and 0.56 mL of BF3-Et20 was added dropwise with stirring. After the addition was completed, the system was continuously stirred in an ice bath for 3 h. Water was added to quench the reaction, the two phases were separated, the aqueous phase was extracted with DCM twice, the organic phase was combined and concentrated under reduced pressure to remove the solvent. The residue was column chromatographed (petroleum ether / ethyl acetate = 3:1-0:1) to obtain 660 mg of yellow oil. The total yield of the two-step reaction was 57%, and the ee value was 89.7%. (c 0.5, EtOH). 1 H NMR (400 MHz, CDC13) δ 7.31 - 7.25 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.59 - 4.52 (m, 1H), 3.99 (s, 2H), 3.89 - 3.73 (m, 4H), 2.38 - 1.89 (m, 4H). 13 C NMR (101 MHz, CDC13) δ 156.5, 141.1, 133.6, 133.1, 131.5, 130.9, 130.6, 130.1, 120.5, 116.3, 76.4, 64.2, 59.0, 38.2, 33.8. HRMS (ESI) Calcd for C 17 H 19 BrClO3([M+H] + ): 385.0201; Found: 385.0199. HPLC conditions: Chiralcel IC-3 column (25 cm x 0.46 cm ID); n-hexane / 2-propanol = 90:10; temp, rt; flow rate = 1.0 mL / min; 210 nm UV detector; t R (R) = 12.0 min (minor); t R (S) = 13.7 min (major).

Claims

1. A compound of formula a, formula a-1, formula b, formula c, having the structure: wherein X is halogen.

2. A method for preparing a chiral alcohol compound, characterized by: Prepared from a compound of formula a or a compound of formula a-1 by an asymmetric catalytic process, wherein X is halogen; The asymmetric catalytic process is carried out in the presence of a chiral catalyst having the structure: wherein Ar is 3,5-di-tert-butylphenyl.

3. The method of claim 2, wherein: The compound of formula a is prepared from compound 2 and compound 3 by a Friedel-Crafts acylation reaction, wherein X is halogen.

4. The method of claim 2, wherein: The compound of formula a-1 is prepared from a compound of formula a by a reduction reaction in the presence of a reducing agent, wherein X is halogen.

5. The method of claim 3, wherein: The Friedel-Crafts acylation reaction is carried out at a temperature ranging from 50°C to 150°C.

6. The method of claim 2, wherein: The compound of formula c is prepared into a compound of formula d, an intermediate of empagliflozin, by a dehydration ring-closing reaction, wherein X is halogen.

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