Preparation method of 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene

Abstract

This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing 1-chloro-4-(β-D-glucopyrano-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene. The method specifically includes the following steps: compound A undergoes dimethyl ketal protection of its carbonyl group to generate compound B; D-gluconate-1,5-lactone reacts with trimethylchlorosilane to synthesize 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone, which then reacts with compound B to synthesize compound C; compound C undergoes deprotection to synthesize compound D; and compound D undergoes a reduction reaction to synthesize compound E. The preparation method of this invention reduces the amount of raw materials used, decreases the amount of byproducts generated in the reaction, increases the reaction yield, and significantly reduces costs, possessing advantages for commercial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene. Background Technology

[0002] CN 101193903A discloses a synthesis method, the synthesis route of which is as follows:

[0003] ;

[0004] In the fourth step of this method, compound 4 undergoes a halide-lithium exchange with a tert-butyllithium reagent and then reacts with 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone. Due to the strong acidity of the hydrogen atom on the carbon atom between the two benzene rings, a large amount of tert-butyllithium is consumed, and an ultra-low temperature of -78°C is required for the reaction to proceed. The reaction yield is low, there are many byproducts, and the tert-butyllithium used is highly hazardous, making it difficult to scale up for production. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene. This preparation method has the advantages of low cost, safe and stable process, high yield, and suitability for large-scale production.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] A method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene, the chemical reaction formula is as follows:

[0008] Specifically, the following steps are included:

[0009] 1) Compound A undergoes dimethyl ketal protection of the carbonyl group to generate compound B;

[0010] 2) D-gluconate-1,5-lactone reacts with trimethylchlorosilane to synthesize 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone, which is then reacted with compound B to synthesize compound C;

[0011] 3) Compound C was deprotected in an organic solvent to synthesize compound D;

[0012] 4) Compound D was reduced in an organic solvent to synthesize compound E.

[0013] Further, the specific steps in step 1) are as follows: (MeO)3CH, acid catalyst and compound A are added to a protic solvent, stirred and heated to reflux for 2-3 hours until the reaction is complete, and then compound B is obtained through post-treatment.

[0014] Furthermore, the protic solvent is selected from methanol, ethanol, and isopropanol.

[0015] Furthermore, the acid catalyst is selected from p-toluenesulfonic acid, methanesulfonic acid, and p-nitrobenzenesulfonic acid.

[0016] Furthermore, the protic solvent is methanol, the acid catalyst is p-toluenesulfonic acid, and the molar ratio of compound A to (MeO)3CH and p-toluenesulfonic acid is 1:1.1~1.5:0.1~0.5.

[0017] Further, the specific steps in step 2) are as follows: D-gluconic acid-1,5-lactone and an organic base are added to tetrahydrofuran, the temperature is lowered to -5℃~5℃, trimethylchlorosilane is added dropwise, and the reaction is carried out at room temperature for 1~2 hours until the reaction is complete. After post-treatment, the mixture is mixed with compound B in tetrahydrofuran solvent and then cooled to -10~-20℃. Then, lithium metal reagent is added dropwise to carry out the reaction and synthesize compound C.

[0018] Furthermore, the organic base is selected from N-methylmorpholine, pyridine, and triethylamine.

[0019] Furthermore, the lithium metal reagent is selected from one of n-butyllithium and tert-butyllithium.

[0020] Furthermore, the organic base is N-methylmorpholine, the lithium metal reagent is n-butyllithium, and the molar ratio of compound B to D-glucono-1,5-lactone and n-butyllithium is 1:1.1~1.3:1.1~1.2.

[0021] Furthermore, the specific steps in step 3) are as follows: compound C and an acid catalyst are added to a protic solvent, and after the reaction is completed at room temperature, compound D is synthesized through post-processing.

[0022] Furthermore, the protic solvent is selected from methanol, ethanol, and isopropanol.

[0023] Furthermore, the acid catalyst is selected from p-toluenesulfonic acid, methanesulfonic acid, and p-nitrobenzenesulfonic acid.

[0024] Furthermore, the protic solvent is methanol, the acid catalyst is p-toluenesulfonic acid, and the molar ratio of compound C to p-toluenesulfonic acid is 1:1.1~1.5.

[0025] Furthermore, the specific steps in step 4) are as follows: Compound D and triethylsilane are reduced in tetrahydrofuran by a boron reagent, and then post-treated to synthesize compound E.

[0026] Furthermore, the boron reagent is selected from one of borane-tetrahydrofuran, lithium borohydride, and boron trifluoride.

[0027] Furthermore, the boron reagent is boron trifluoride, and the molar ratio of compound D to boron trifluoride is 1:2.1~2.5.

[0028] The beneficial effects of adopting the technical solution of the present invention are:

[0029] In this invention, compound C (5-bromo-2-chlorophenyl)[4-[(tetrahydro-3-furanyl)oxy]phenyl] ketone is protected with a dimethyl ketal, which avoids excessive consumption of lithium metal reagent in the next reaction. Furthermore, the compound protected with the dimethyl ketal can be reacted with n-butyllithium instead of tert-butyllithium, avoiding the use of highly reactive and hazardous tert-butyllithium. This increases the reaction temperature, reduces the demand on production equipment, and results in a stable process with small byproducts and high yield, making it suitable for commercial production. Detailed Implementation

[0030] The following describes a method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to specific embodiments of the present invention.

[0031] Example 1: Synthesis of Compound A

[0032] The synthesis route is as follows:

[0033] ;

[0034] Refer to Examples II and IV of Patent Publication No. CN 101193903A, "Method for preparing pyranose-substituted benzylbenzene derivatives and intermediates thereof".

[0035] Example 2: Synthesis of Compound B

[0036] The synthesis route is as follows:

[0037] ;

[0038] 1.80 g (0.20 eq) p-toluenesulfonic acid, 20.00 g (1.00 eq) compound A, and 6.67 g (1.20 eq) (MeO)3CH were added to 250 mL of methanol. The mixture was stirred and heated to reflux for 2 hours. TLC monitoring showed no residual starting material. The mixture was cooled to below 30 °C, and 500 mL of water was added. The mixture was extracted twice with 300 mL of ethyl acetate. The combined organic phases were washed with 250 mL of saturated sodium chloride solution. The organic phase was desolvated under reduced pressure to give 19.05 g of white solid compound B. Yield: 85.0%, HPLC: 99.36%.

[0039] Example 3: Synthesis of Compound C

[0040] The synthesis route is as follows:

[0041] ;

[0042] Add 22.80 g (1.10 eq) D-gluconic acid-1,5-lactone and 58.85 g (5.00 eq) N-methylmorpholine to 200 mL of tetrahydrofuran, and cool to -5 °C under nitrogen protection. Then add 56.88 g (4.50 eq) trimethylchlorosilane dropwise, maintaining the temperature between -5 and 5 °C. After the addition is complete, stir the reaction mixture overnight at room temperature. Add 300 mL of toluene to the reaction mixture, and slowly add 500 mL of ice water under an ice-water bath to keep the temperature below 10 °C. Separate the organic phase and wash with an aqueous solution of sodium dihydrogen phosphate, water, and brine. Remove the solvent from the organic phase under reduced pressure, and remove residual solvent and water by entrainment with tetrahydrofuran. Add 300 mL of tetrahydrofuran and 50.00 g (1.00 eq) of compound B to the concentrate, and stir under nitrogen, cooling to -20 to -10 °C. 64 mL (1.10 eq) of 2.0 M n-butyllithium / tetrahydrofuran solution was slowly added to the reaction solution. After the addition was complete, the reaction was carried out at -20 to -10 °C for 1 h. After quenching with saturated ammonium chloride, the mixture was extracted with ethyl acetate and dissolved under reduced pressure to obtain crude compound C. The next reaction was carried out according to the theoretical yield of 100%.

[0043] Example 4: Synthesis of Compound D

[0044] The synthesis route is as follows:

[0045] ;

[0046] 200 mL of methanol was added to dissolve the crude compound C prepared in Example 3, and 26.17 g (1.30 eq) of p-toluenesulfonic acid was added. The mixture was reacted overnight at room temperature, and then the reaction solution was neutralized with solid sodium bicarbonate. After desolventizing under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. After drying with sodium sulfate, the mixture was filtered and washed, and desolventized under reduced pressure to obtain 53.23 g of crude compound D. Yield: 92.1%, HPLC: 95.60%.

[0047] Example 5: Synthesis of Compound E

[0048] The synthesis route is as follows:

[0049] ;

[0050] Add 40 mL of dichloromethane and 80 mL of acetonitrile to a reaction flask, then add 20.00 g (1.00 eq) of crude compound D and 13.5 mL of triethylsilane. Add 4.5 mL (2.20 eq) of boron trifluoride / tetrahydrofuran solution dropwise at -10 to 0 °C. After the addition is complete, react at 0-5 °C for 3 h. No starting material was detected by TLC. The reaction was quenched with sodium bicarbonate solution, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure, and recrystallized from ethanol to give 16.65 g of white crystalline compound E. Yield: 91.8%, HPLC: 99.58%.

[0051] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent claim. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene, characterized in that: The chemical reaction formula is as follows: ； Specifically, the following steps are included: 1) Compound A undergoes dimethyl ketal protection of the carbonyl group to generate compound B; 2) D-gluconate-1,5-lactone reacts with trimethylchlorosilane to synthesize 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone, which is then reacted with compound B to synthesize compound C; 3) Compound C is deprotected to synthesize compound D; 4) Compound D undergoes a reduction reaction to synthesize compound E; The specific steps in step 2) are as follows: D-gluconic acid-1,5-lactone and an organic base are added to tetrahydrofuran, the temperature is lowered to -5℃~5℃, trimethylchlorosilane is added dropwise, and the reaction is carried out at room temperature for 1~2 hours until the reaction is complete. After post-treatment, the mixture is mixed with compound B in tetrahydrofuran solvent and then cooled to -10~-20℃. Then, lithium metal reagent is added dropwise to carry out the reaction and synthesize compound C. The organic base is selected from one of N-methylmorpholine, pyridine, and triethylamine; The lithium metal reagent is n-butyllithium; The specific steps in step 3) are as follows: compound C and acid catalyst are added to a protic solvent, and after the reaction is completed at room temperature, compound D is synthesized through post-processing. The protic solvent is methanol; The acid catalyst is selected from one of p-toluenesulfonic acid, methanesulfonic acid, and p-nitrobenzenesulfonic acid.

2. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 1, characterized in that: The specific steps in step 1) are as follows: (MeO)3CH, acid catalyst and compound A are added to a protic solvent, stirred and heated to reflux for 2-3 hours until the reaction is complete, and then compound B is obtained after post-treatment. The protic solvent is selected from one of methanol, ethanol, and isopropanol; The acid catalyst is selected from one of p-toluenesulfonic acid, methanesulfonic acid, and p-nitrobenzenesulfonic acid.

3. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 2, characterized in that: In step 1), the protic solvent is methanol, the acid catalyst is p-toluenesulfonic acid, and the molar ratio of compound A to (MeO)3CH and p-toluenesulfonic acid is 1:1.1~1.5:0.1~0.

5.

4. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 1, characterized in that: In step 2), the organic base is N-methylmorpholine, and the molar ratio of compound B to D-glucono-1,5-lactone and n-butyllithium is 1:1.1~1.3:1.1~1.

2.

5. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 1, characterized in that: In step 3), the acid catalyst is p-toluenesulfonic acid, and the molar ratio of compound C to p-toluenesulfonic acid is 1:1.1~1.

5.

6. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 1, characterized in that: The specific steps in step 4) are as follows: Compound D and triethylsilane are reduced in tetrahydrofuran by a boron reagent, and then post-treated to synthesize compound E.

7. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 6, characterized in that: In step 4), the boron reagent is selected from one of borane-tetrahydrofuran, lithium borohydride, and boron trifluoride.

8. The method for preparing 1-chloro-4-(β-D-pyranoglucopyran-1-yl)-2-(4-tetrahydrofuran-3-yloxy-benzyl)-benzene according to claim 6, characterized in that: In step 4), the boron reagent is boron trifluoride, and the molar ratio of compound D to boron trifluoride is 1:2.1~2.5.

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