Method for simply and efficiently preparing gliflozin thioglycoside

Abstract

The invention discloses a simple and efficient method for preparing gliflozin thioglycoside. Gliflozin thioglycoside is an SGLT2 (sodium glucose transporter 2) inhibitor with a novel molecular structure and a potential medicine for treating type 2 diabetes mellitus. The structural general formula of the gliflozin thioglycoside is as follows: # imgabs0 #. The preparation method of the gliflozin thioglycoside comprises the following two steps: 1, directly carrying out sulfur-carbon coupling reaction on 1-glucosinolate protected by peracetyl in a solvent under the action of alkali and a palladium catalyst to prepare a tetra-acetyl protected gliflozin thioglycoside product; and step 2, carrying out deacetylation on the tetra-acetyl protected gliflozin thioglycoside to prepare the gliflozin thioglycoside. The method is mild in reaction condition, simple and convenient to operate, relatively green and high in yield.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and sugar chemical synthesis, and particularly relates to a simple and efficient method for preparing glucosinolate gliflozin. Background Art

[0002] Gliflozin drugs are all drugs for the treatment of type 2 diabetes developed based on the glucoside molecule. Its mechanism of action is to inhibit the transport of glucose by SGLT-2 (sodium glucose transporter type 2) in the kidneys to achieve the purpose of lowering blood sugar. Since these drugs have no risk of hypoglycemia when lowering blood sugar, and have the advantages of reducing weight and protecting the kidneys and cardiovascular system, empagliflozin and dapagliflozin have become the two best-selling drugs for the treatment of type 2 diabetes in the world. The half-inhibitory concentration of empagliflozin for SGLT2 reported in the literature is 3.1nM, and its global sales have increased from approximately US$4.1 billion in 2021 to US$8.4 billion in 2022 and US$10.6 billion in 2023. In the global small molecule drug sales ranking, empagliflozin rose from 9th in 2021 to 5th in 2022 and 3rd in 2023. The half-inhibitory concentration of dapagliflozin for SGLT2 reported in the literature is 1.2 nM, and its global sales have increased from approximately US$2.1 billion in 2021 to US$4.4 billion in 2022 and US$5.9 billion in 2023. In the global small molecule drug sales ranking, dapagliflozin rose from 32nd in 2021 to 13th in 2022 and 10th in 2023.

[0003] Although many glucose oxygen glycoside derivatives are also SGLT2 inhibitors, they are easily hydrolyzed by β-glucosidase in the small intestine and ultimately cannot be made into medicines. In the end, because the molecular structure of carbon glycoside gliflozin is stable and it is not hydrolyzed by β-glucosidase in the small intestine, it is developed into a medicine. The inventors of this application have speculated that glucose glucosidase derivatives are not hydrolyzed by β-glucosidase either. If they are SGLT-2 inhibitors, they may also be developed into gliflozin drugs for the treatment of type 2 diabetes. Based on this, the inventors of this application disclosed a green and efficient method for preparing fully acyl-protected 1-thioglucose and glucose 1-thiol in invention patent 202011424879.4. Subsequently, in invention patent 202210604837.1, the inventors of this application used the coupling of tetraacetylated glucose 1-thiol with aryl iodide under palladium catalysis to efficiently synthesize a class of glucosidase gliflozin with high SGLT2 inhibitory activity. The inventors of this application have tested the resistance to β-glucosidase hydrolysis, cytotoxicity, SGLT2 inhibitory activity at the in vitro cell level and oral glucose-lowering tests on these glucosidase gliflozins. The results show that these glucosidase gliflozins are resistant to β-glucosidase hydrolysis, non-cytotoxic, have low SGLT2 half-inhibitory concentrations and good in vivo glucose-lowering activity (Feng, G.-J.; Dong, H.; et al. J. Med. Chem. 2023, 66, 12536). Its specific synthesis route, chemical structure and corresponding half-inhibitory concentration for SGLT2 are shown in Formula 1 and Formula 2:

[0004] Summary of the invention

[0005] In view of the problem that the prior art first uses fully acetyl-protected 1-thioglucose to synthesize tetraacetylated glucose 1-thiol, and then uses tetraacetylated glucose 1-thiol as a raw material to synthesize glucosinolate gliflozin, there are complicated steps. The object of the present invention is to provide a simple and efficient method for preparing glucosinolate gliflozin, that is, directly using fully acetyl-protected 1-thioglucose as a raw material to synthesize glucosinolate gliflozin, omitting the synthesis step of tetraacetylated glucose 1-thiol intermediate.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] In one aspect, the present invention provides a class of glucosinolate gliflozin, the molecular structure of the glucosinolate gliflozin is shown in Formula 3 below:

[0008]

[0009] Wherein, R1 is one or more of hydrogen, alkyl, and halogen; and R2 is aryl.

[0010] Preferably, the alkyl group is any one of methyl, ethyl, halomethyl or haloethyl.

[0011] Preferably, the halogen is any one of iodine, bromine, chlorine, fluorine and the like.

[0012] Preferably, the aryl group is Any one or more of the above.

[0013] Preferably, the glucosinolate gliflozin is any one or more of glucosinolate sergliflozin, glucosinolate dapagliflozin, glucosinolate empagliflozin, glucosinolate canagliflozin, glucosinolate bagliflozin, and the like.

[0014] On the other hand, the present invention also provides a simple and efficient method for preparing the glucosinolate gliflozin, comprising the following steps:

[0015] (1) Preparation of tetraacetyl protected glucosinolate gliflozin: fully acetyl protected 1-thioglucose, iodoaryl derivative, palladium catalyst and carbonate are dissolved in dimethylformamide (DMF) in proportion, and then the resulting mixture is reacted at 50° C. for 2 to 6 hours, concentrated and extracted with dichloromethane and deionized water, and then the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl protected glucosinolate gliflozin;

[0016] (2) Preparation of glucosinolate gliflozin: The tetraacetyl-protected glucosinolate gliflozin obtained in step (1) is dissolved in a sodium hydroxide methanol solution, stirred at room temperature for 2 to 4 hours, and neutralized by adding a hydrogen ion exchange resin, filtered, concentrated, and purified by column chromatography to obtain glucosinolate gliflozin.

[0017] Specifically, the chemical reaction equation involved in step (1) is shown in the following formula (4):

[0018]

[0019] Specifically, the chemical reaction equation involved in step (2) is shown in Formula 5 below:

[0020]

[0021] Preferably, in the step (1), the ratio of the fully acetyl-protected 1-thioglucose to dimethylformamide is 0.1-0.2 mol:1L.

[0022] Preferably, in step (1), the molar ratio of the fully acetyl-protected 1-thioglucose, the iodinated aryl derivative, and the carbonate is 1:0.5-1.5:1.0-2.0.

[0023] Preferably, in step (1), the molar ratio of the fully acetyl-protected 1-thioglucose to the palladium catalyst is 1:0.02-0.06.

[0024] Preferably, in step (1), the structural formula of the iodinated aryl derivative is as shown in Formula VI below:

[0025]

[0026] Wherein: R1 is any one or more of hydrogen, alkyl, and halogen; and R2 is aryl.

[0027] More preferably, the alkyl group is any one of methyl, ethyl, halomethyl or haloethyl.

[0028] More preferably, the halogen is any one of iodine, bromine, chlorine, fluorine and the like.

[0029] More preferably, the aryl group is Any one or more of the above.

[0030] Preferably, in step (1), the structure of the palladium catalyst is as shown in Formula VII below:

[0031]

[0032] Preferably, in step (1), the carbonate is any one or more of potassium carbonate, sodium carbonate and cesium carbonate.

[0033] Preferably, in step (2), the concentration of the sodium hydroxide methanol solution is 0.007-0.013 mol / L, more preferably 0.01 mol / L.

[0034] Preferably, in the step (2), the amount of methanol in the sodium hydroxide methanol solution is 5 mL / mmol of the tetraacetyl-protected glucosinolate gliflozin.

[0035] Specifically, in step (2), room temperature refers to natural room temperature conditions in all seasons without additional cooling or heating treatment. Normally, room temperature is controlled at 10-30°C, preferably 15-25°C.

[0036] Preferably, in step (1) and step (2), the inert atmosphere is nitrogen or argon.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] 1. The present invention provides a more concise and efficient method for synthesizing gliflozin glucosides. In the prior art, the synthesis of gliflozin glucosides using fully acetyl-protected 1-thioglucose as a raw material requires three-step reactions, namely, the selective deacylation of fully acetyl-protected 1-thioglucose to synthesize tetraacetylated glucose 1-thiol, the sulfur-carbon coupling of tetraacetylated glucose 1-thiol under palladium catalysis to synthesize tetraacetyl-protected gliflozin glucosides and the deacetylation of tetraacetyl-protected gliflozin glucosides to synthesize gliflozin glucosides. In the present invention, the synthesis of gliflozin glucosides using fully acetyl-protected 1-thioglucose as a raw material only requires two-step reactions, namely, the sulfur-carbon coupling of fully acetyl-protected 1-thioglucose under palladium catalysis to synthesize tetraacetyl-protected gliflozin glucosides and the deacetylation of tetraacetyl-protected gliflozin glucosides to synthesize gliflozin glucosides. The present invention simplifies the reaction process, omits the separation, purification and preparation of tetraacetylated glucose 1-thiol, and thus greatly reduces the synthesis cost of gliflozin glucosides.

[0039] 2. Compared with the method for synthesizing glucosinolate gliflozin, the method for synthesizing glucosinolate gliflozin provided by the present invention has mild reaction conditions, fewer synthesis steps, higher total yield, lower synthesis cost, and has good prospects for development into medicines. DETAILED DESCRIPTION

[0040] The present invention provides a simple and efficient method for preparing gliflozin glucosinolate. gliflozin glucosinolate is a class of SGLT2 (sodium glucose transporter type 2) inhibitors with novel molecular structures and potential drugs for treating type 2 diabetes. The preparation method of gliflozin glucosinolate comprises two steps: the first step is to directly subject fully acetyl-protected 1-thioglucose to a sulfur-carbon coupling reaction in a solvent and under the action of a base and a palladium catalyst to obtain a tetraacetyl-protected gliflozin glucosinolate product; the second step is to deacylate the tetraacetyl-protected gliflozin glucosinolate to obtain gliflozin glucosinolate. The method of the present invention has mild reaction conditions, is easy to operate, is relatively green, and has a high yield.

[0041] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail below in conjunction with embodiment. Of course, the specific embodiments described herein are only used to explain the present invention. Those skilled in the art should understand that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0042] Although the steps in the present invention are arranged with numbers, they are not used to limit the order of the steps. Unless the order of the steps is clearly stated or the execution of a certain step requires other steps as a basis, the relative order of the steps can be adjusted. It is understood that the term "and / or" used in the present invention involves and covers any and all possible combinations of one or more of the associated listed items.

[0043] Unless otherwise specified, the chemical reagents and materials in the present invention are purchased from commercial sources or synthesized from raw materials purchased from commercial sources.

[0044] The structure of the palladium catalyst used in the following embodiments of the present invention is shown in Formula 7 of the present invention.

[0045] Example 1

[0046] A simple and efficient method for preparing sergliflozin glucosinolate comprises the following steps:

[0047] (1) Under nitrogen protection, add fully acetyl-protected 1-thioglucose (203 mg, 0.5 mmol), potassium carbonate (124 mg, 0.9 mmol), iodobenzene derivative E (243 mg, 0.75 mmol) and palladium catalyst (19 mg, 0.02 mmol) into a bottle, and then add DMF (4 mL). After the mixture is stirred evenly, react at 50° C. for 3 hours. The reaction mixture is concentrated and extracted with dichloromethane and deionized water, and the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl-protected glucosinolate sergliflozin (84%, 237 mg).

[0048] (2) The product obtained in step (1) (237 mg, 0.42 mmol) was dissolved in sodium hydroxide methanol solution (1 mL, 0.01 M). The reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. The mixture was then precipitated with Amberlite IR-120 (H + ) ion exchange resin neutralized and filtered, concentrated. Column chromatography gave sergliflozin A (97%, 159 mg). 1H NMR (400 MHz, CD3OD): δ7.70–7.68 (m, 1H), 7.19–7.17 (m, 2H), 7.13–7.10 (m, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 4.59 (d, J = 9.7 Hz, 1H), 4.14 (S, 2H), 3.85 (dd, J = 12.1, 2.1 Hz, 1H), 3.74 (S, 3H), 3.66 (dd, J = 12.1, 5.2 Hz, 1H), 3.40-3.33 (m, 2H), 3.29–3.25 (m, 2H).

[0049] Among them, the structures of iodobenzene derivative E and glucosinolate sergliflozin A are shown below:

[0050]

[0051] Example 2

[0052] A simple and efficient method for preparing dapagliflozin glucosinolate comprises the following steps:

[0053] (1) Under nitrogen protection, add fully acetyl protected 1-thioglucose (203 mg, 0.5 mmol), cesium carbonate (261 mg, 0.8 mmol), iodobenzene derivative F (224 mg, 0.6 mmol) and palladium catalyst (19 mg, 0.02 mmol) into the bottle, and then add DMF (3 mL). After the mixture is stirred evenly, react at 50°C for 4 hours. After the reaction mixture is concentrated, it is extracted with dichloromethane and deionized water, and the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl protected glucosinolate dapagliflozin (87%, 265 mg).

[0054] (2) The product obtained in step (1) (265 mg, 0.44 mmol) was dissolved in sodium hydroxide methanol solution (1 mL, 0.01 M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The mixture was then precipitated with Amberlite IR-120 (H + ) ion exchange resin, filtered and concentrated. Column chromatography gave dapagliflozin B (99%, 188 mg). 1HNMR (400MHz, CD3OD): δ7.68(d,J=7.9Hz,1H),7.31(d,J=7.9Hz,1H),7.19(t,J=8.0Hz,1H),6.99(d,J=8.3Hz,2H),6.74(d,J=8.6Hz,2H),4.61(d, J=9.7Hz,1H),4.42–4.31(m,2H),3.99–3.94(m,2H),3.83(d,J=12.4Hz,1H ),3.64(dd,J=12.1,4.9Hz,1H),3.38-3.22(m,4H),1.33(t,J=7.0Hz,3H).

[0055] Among them, the structures of iodobenzene derivative F and glucosinolate dapagliflozin B are as follows:

[0056]

[0057] Example 3

[0058] A simple and efficient method for preparing empagliflozin glucosinolate comprises the following steps:

[0059] (1) Under nitrogen protection, add fully acetyl protected 1-thioglucose (203 mg, 0.5 mmol), sodium carbonate (106 mg, 1 mmol), iodobenzene derivative G (228 mg, 0.55 mmol) and palladium catalyst (24 mg, 0.025 mmol) into the bottle, and then add DMF (5 mL). After the mixture is stirred evenly, react at 50°C for 5 hours. The reaction mixture is concentrated and extracted with dichloromethane and deionized water, and the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl protected glucosinolate dapagliflozin (87%, 285 mg).

[0060] (2) The product obtained in step (1) (285 mg, 0.44 mmol) was dissolved in sodium hydroxide methanol solution (1 mL, 0.01 M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The mixture was then precipitated with Amberlite IR-120 (H + ) ion exchange resin neutralized and filtered and concentrated. After column chromatography, glucosinolate empagliflozin C (99%, 210 mg) was obtained. 1HNMR (400MHz, CD3OD): δ7.69 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 4.93 (s, 1H), 4.61 (d, J = 9.7 Hz, 1H), 4.42-4.31 (m, 2H), 3.95-3.81 (m, 5H), 3.65 (dd, J = 12.0, 4.9 Hz, 1H), 3.38-3.22 (m, 4H), 2.23-2.04 (m, 1H).

[0061] Among them, the structures of iodobenzene derivative G and glucosinolate empagliflozin C are shown below:

[0062]

[0063] Example 4

[0064] A simple and efficient method for preparing canagliflozin glucosinolate comprises the following steps:

[0065] (1) Under nitrogen protection, add fully acetyl protected 1-thioglucose (203 mg, 0.5 mmol), potassium carbonate (124 mg, 0.9 mmol), iodobenzene derivative H (226 mg, 0.55 mmol) and palladium catalyst (24 mg, 0.025 mmol) into the bottle, and then add DMF (5 mL). After the mixture is stirred evenly, react at 50°C for 5 hours. After the reaction mixture is concentrated, it is extracted with dichloromethane and deionized water, and the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl protected glucosinolate canagliflozin (84%, 269 mg).

[0066] (2) The product obtained in step (1) (269 mg, 0.42 mmol) was dissolved in sodium hydroxide methanol solution (1 mL, 0.01 M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The mixture was then precipitated with Amberlite IR-120 (H + ) ion exchange resin neutralized and filtered and concentrated. Column chromatography gave canagliflozin D (97%, 195 mg). 1HNMR (400 MHz, CD3OD): δ7.66 (dd, J = 7.2, 2.1 Hz, 1H), 7.55–7.48 (m, 2H), 7.21–7.13 (m, 2H), 7.10–7.02 (m, 3H), 6.61 (d, J = 3.5 Hz, 1H), 4.66–4.45 (m, 2H), 3.85 (dd, J = 12.1, 2.2 Hz, 1H), 3.67 (dd, J = 12.1, 5.4 Hz, 1H), 3.42–3.21 (m, 5H), 2.35 (s, 3H).

[0067] Among them, the structures of iodobenzene derivative H and glucosinolate canagliflozin D are shown below:

[0068]

[0069] Example 5

[0070] A simple and efficient method for preparing glucosinolate bagliflozin comprises the following steps:

[0071] (1) Under nitrogen protection, add fully acetyl-protected 1-thioglucose (203 mg, 0.5 mmol), potassium carbonate (124 mg, 0.9 mmol), iodobenzene derivative I (321 mg, 0.75 mmol) and palladium catalyst (29 mg, 0.03 mmol) into a bottle, and then add DMF (5 mL). After the mixture is stirred evenly, react at 50° C. for 6 hours. The reaction mixture is concentrated and extracted with dichloromethane and deionized water, and the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl-protected glucosinolate bagliflozin (84%, 279 mg).

[0072] (2) The product obtained in step (1) (279 mg, 0.42 mmol) was dissolved in sodium hydroxide methanol solution (1 mL, 0.01 M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen protection. The mixture was then precipitated with Amberlite IR-120 (H + ) ion exchange resin, filtered and concentrated. Column chromatography gave glucosinolate bagliflozin J (98%, 204 mg). 1HNMR (400MHz, CD3OD): δ7.71(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),7.23(t,J=8.3Hz,1H),7.04(d,J=8.3Hz,2H),6.8(d,J=8.3Hz,2H),4.63(d,J= 10Hz,1H),4.38(dd,J=14.7,30Hz,2H),4.08–4.02(m,2H),3.90–3.80(m,3 H).3.67(dd,J=12.1,5.4Hz,1H),3.44–3.22(m,5H),0.61–0.46(m,4H).13C NMR(101MHz,CD3OD)δ157.1,138.9,137.3,134.9,131.3,130.1,129.0,128.0,1 27.6,114.0,88.1,80.1,78.3,72.6,69.9,68.8,66.9,61.4,53.0,36.7,4.6ppm.

[0073] Among them, the structures of iodobenzene derivative I and glucosinolate bagliflozin J are shown below:

[0074]

[0075] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A class of glucosinolate gliflozin, characterized in that: The molecular structure formula of the glucosinolate gliflozin is shown in Formula 3 below: Wherein, R1 is one or more of hydrogen, alkyl, and halogen; and R2 is aryl.

2. The glucosinolate gliflozin according to claim 1, characterized in that: The alkyl group is any one of methyl, ethyl, halogenated methyl or halogenated ethyl; the halogen group is any one of iodine, bromine, chlorine and fluorine; the aryl group is Any one or more of .

3. A simple and efficient method for preparing the glucosinolate gliflozin according to claim 1 or 2, characterized in that: The following steps are involved: (1) Preparation of tetraacetyl protected glucosinolate gliflozin: fully acetyl protected 1-thioglucose, iodoaryl derivative, palladium catalyst and carbonate are dissolved in dimethylformamide (DMF) in proportion, and then the resulting mixture is reacted at 50° C. for 2 to 6 hours, concentrated and extracted with dichloromethane and deionized water, and then the organic phase is concentrated and purified by column chromatography to obtain tetraacetyl protected glucosinolate gliflozin; (2) Preparation of glucosinolate gliflozin: The tetraacetyl-protected glucosinolate gliflozin obtained in step (1) is dissolved in a sodium hydroxide methanol solution, stirred at room temperature for 2 to 4 hours, and neutralized by adding a hydrogen ion exchange resin, filtered, concentrated, and purified by column chromatography to obtain glucosinolate gliflozin.

4. The method according to claim 3, characterized in that: In step (1), the ratio of the fully acetyl-protected 1-thioglucose to dimethylformamide is 0.1-0.2 mol:1L.

5. The method according to claim 3, characterized in that: In step (1), the molar ratio of the fully acetyl-protected 1-thioglucose, the iodinated aryl derivative, and the carbonate is 1:0.5-1.5:1.0-2.

0.

6. The method according to claim 3, characterized in that: In the step (1), the molar ratio of the fully acetyl-protected 1-thioglucose to the palladium catalyst is 1:0.02-0.

06.

7. The method according to claim 3, characterized in that: In the step (1), the structural formula of the iodinated aryl derivative is shown in Formula VI below: Wherein: R1 is any one or more of hydrogen, alkyl, and halogen; and R2 is aryl.

8. The method according to claim 3, characterized in that: In the step (1), the structure of the palladium catalyst is shown in the following formula VII:

9. The method according to claim 3, characterized in that: In the step (2), the concentration of the sodium hydroxide methanol solution is 0.007 to 0.013 mol / L.

10. The method according to claim 3, characterized in that: In the step (2), the amount of methanol in the sodium hydroxide methanol solution is 5 mL / mmol of the tetraacetyl-protected glucosinolate gliflozin.

Images