A 3-deoxydapagliflozin intermediate compound and its preparation method and application

Abstract

The present invention discloses a 3-deoxydapagliflozin intermediate compound and a preparation method and application thereof. The 3-deoxydapagliflozin intermediate compound provided by the present invention has a structure shown in Formula I: The present invention provides a 3-deoxydapagliflozin intermediate compound with a novel structure. The preparation of 3-deoxydapagliflozin by using the intermediate compound can shorten the synthesis steps, improve the yield of 3-deoxydapagliflozin, and is suitable for large-scale preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a 3-deoxydapagliflozin intermediate compound and a preparation method and application thereof. Background Art

[0002] As a new target for the treatment of diabetes, sodium-glucose co-transporter 2 (SGLT2) has shown significant advantages in the treatment of type 2 diabetes. SGLT2 inhibitors inhibit the reabsorption of glucose by the kidneys, allowing excess glucose to be excreted from the urine, thereby lowering blood sugar. This mechanism of action provides a new approach for the treatment of diabetes and has become a hot topic in the research of hypoglycemic drugs. Currently, a number of SGLT2 inhibitors have been approved for the treatment of type 2 diabetes worldwide, including Canagliflozin, Dapagliflozin, Empagliflozin, etc. These drugs have been shown to lower blood sugar, reduce weight, lower blood pressure, etc. in clinical applications, and also have certain benefits for cardiovascular and renal protection.

[0003] Chinese patent CN 103864737A discloses a method for preparing the above-mentioned 3-deoxydapagliflozin, which is to use dapagliflozin as a raw material, react with PhCH(OMe) in the presence of a catalyst, and then 2 Reaction, reaction with tert-butyldimethylchlorosilane (TBDMSCl) under alkaline conditions, reaction with acetic anhydride under alkaline conditions, deprotection in a hydrogen fluoride pyridine reagent, reaction with iodine under the catalysis of triphenylphosphine, deprotection under the catalysis of camphorsulfonic acid, acetylation reaction with acetic anhydride, hydrogenation reduction under the catalysis of palladium hydroxide, and finally deacetylation under alkaline conditions to obtain the compound 3-deoxydapagliflozin; the reaction equation is as follows.

[0004]

[0005] In summary, this route has obvious defects: (1) The synthetic route is long, with a total of 9 steps, the process is relatively complex, and the controllability is poor; (2) The total yield is low, only 29%; (3) Due to the strong corrosiveness and toxicity of the hydrogen fluoride pyridine reagent, it is not suitable for large-scale production. Therefore, it is very necessary to improve the synthetic process and conditions of 3-deoxydapagliflozin and explore a preparation method of 3-deoxydapagliflozin with a short synthetic route and high total yield. Summary of the invention

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides a 3-deoxydapagliflozin intermediate compound, and a new route for preparing 3-deoxydapagliflozin using the intermediate compound, which has a short synthetic route, high yield, and is suitable for large-scale preparation.

[0007] The second aspect of the present invention also provides a method for preparing a 3-deoxydapagliflozin intermediate compound.

[0008] The third aspect of the present invention also provides a use of a 3-deoxydapagliflozin intermediate compound.

[0009] The fourth aspect of the present invention also provides a method for preparing 3-deoxydapagliflozin.

[0010] According to the first aspect of the present invention, a 3-deoxydapagliflozin intermediate compound is provided, which has a structure shown in Formula I:

[0011]

[0012] The 3-deoxydapagliflozin intermediate compound according to the embodiment of the present invention has at least the following beneficial effects:

[0013] The present invention provides a 3-deoxydapagliflozin intermediate compound with a novel structure. The intermediate compound is used to prepare 3-deoxydapagliflozin, which can shorten the synthesis steps, improve the yield of 3-deoxydapagliflozin, and is suitable for large-scale preparation.

[0014] According to the second aspect of the present invention, a method for preparing a 3-deoxydapagliflozin intermediate compound is provided, comprising the following steps:

[0015] Compound 1, an organic solvent, boron trichloride and a chiral tertiary amine are mixed and reacted to obtain;

[0016] Wherein, the structural formula of compound 1 is as follows:

[0017]

[0018] The method for preparing the 3-deoxydapagliflozin intermediate compound according to the embodiment of the present invention has at least the following beneficial effects:

[0019] The present invention uses compound 1 as a raw material, and under the conditions of selecting boron trichloride and a chiral tertiary amine, the reaction can selectively remove the acetyl group on the 3-OH on the glucose ring to obtain the 3-deoxydapagliflozin intermediate compound of the present invention.

[0020] According to some embodiments of the present invention, the chiral tertiary amine is selected from at least one of the following structural formulas:

[0021] Therefore, the preparation method of the present invention has a good yield.

[0022] According to some embodiments of the present invention, the molar ratio of the compound 1 to the chiral tertiary amine is 1:(0.1-1).

[0023] According to some embodiments of the present invention, the molar ratio of the compound 1 to the chiral tertiary amine is 1:(0.5-1). Therefore, the preparation method of the present invention has a good yield.

[0024] According to some embodiments of the present invention, the reaction temperature is -10°C to 20°C.

[0025] According to some embodiments of the present invention, the reaction temperature is -10° C. to 10° C. Therefore, the preparation method of the present invention has a good yield.

[0026] According to some embodiments of the present invention, the organic solvent is selected from at least one of dichloromethane, chloroform or carbon tetrachloride.

[0027] According to some embodiments of the present invention, the compound 1 is prepared by the following method:

[0028] Dapagliflozin is prepared by acetylation with acetic anhydride under base catalysis.

[0029] The third aspect of the present invention provides a use of the 3-deoxydapagliflozin intermediate compound for preparing 3-deoxydapagliflozin.

[0030] The fourth aspect of the present invention provides a method for preparing 3-deoxydapagliflozin, comprising the following steps:

[0031] S1. subjecting the 3-deoxydapagliflozin intermediate compound described in the first aspect of the present invention to iodination reaction to obtain compound 2;

[0032] S2, removing iodine from compound 2 under the action of a reducing agent to obtain compound 3;

[0033] S3, hydrolyzing compound 3 under alkaline conditions to remove the acetyl group to obtain 3-deoxydapagliflozin;

[0034] Among them, the structural formulas of compound 2, compound 3 and 3-deoxydapagliflozin are as follows:

[0035]

[0036] The method for preparing 3-deoxydapagliflozin according to an embodiment of the present invention has at least the following beneficial effects:

[0037] The invention uses a 3-deoxydapagliflozin intermediate compound as a raw material and prepares 3-deoxydapagliflozin through three-step reactions of iodination deoxygenation, reduction and deacetylation. The preparation method has a short synthesis route and a high total yield.

[0038] According to some embodiments of the present invention, the base used in the alkaline condition is selected from at least one of sodium hydroxide, sodium ethoxide, sodium methoxide, potassium hydroxide or lithium hydroxide.

[0039] According to some embodiments of the present invention, the reducing agent includes hydrogen or tri-n-butyltin hydride.

[0040] According to some embodiments of the present invention, the conditions for the iodination reaction include iodine, triphenylphosphine and imidazole.

[0041] Other features and advantages of the present invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0042] The following are specific embodiments of the present invention, and the technical solutions of the present invention are further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0043] Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0044] Preparation of compound 1 in the embodiment of the present invention:

[0045] 4.09 g (10 mmol) of dapagliflozin was dissolved in pyridine (50 mL), 4-dimethylaminopyridine (1.22 g, 10 mmol) was weighed and added to the reaction system, cooled to 0°C with an ice-water bath, and Ac was added dropwise with stirring. 2 O (9.4 mL, 0.1 mol), after the addition was complete, the temperature was raised to room temperature and stirred overnight. The reaction was complete when detected by TLC. The reaction solution was poured into ice water (300 mL), stirred, extracted with EtOAc (50 mL × 3), and the organic phases were combined. The organic phases were washed with 1 mol / L HCl solution (50 mL × 3) and saturated NaCl solution (50 mL × 3) in sequence, and anhydrous MgSO 4 The mixture was dried and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure on a rotary evaporator. The residue was separated and purified by silica gel column chromatography (EtOAc / n-hexane=1 / 4) to obtain compound 1. White solid, 5.48 g, yield 95%.

[0046] The test data are as follows:

[0047] mp124℃-126℃; 1 H NMR (DMSO-d 6 ,400MHz), δ:7.43(d,1H,J=8.0Hz),7.23(d,1H,J

[0048] =8.4Hz),7.22(d,1H,J=0.8Hz),7.04(d,2H,J=8.4Hz),6.82(d,2H,J=8.4Hz),5.35(t,1H,J=9.6Hz),5.07(t,1H,J=9.6Hz),4.94(t,1H,J=9.6 Hz), 4.66 (d, 1H, J = 9.6Hz), 4.00-4.15 (m, 3H), 3.90-4.01 (m, 4H), 2.00 (s, 3H), 1.97 (s, 3H), 1.92 (s, 3H), 1.69 (s, 3H), 1.27 (t, 3H, J = 7.0Hz).

[0049] Example 1

[0050] This example provides a 3-deoxydapagliflozin intermediate compound, and its reaction equation and preparation method are as follows:

[0051]

[0052] Compound 1 (1.15 g, 2 mmol, 1.0 eq) and chiral tertiary amine ( 1.42 g, 9.5 mmol, 1 eq) was dissolved in dry CH 2 Cl 2 (11.5 mL), under nitrogen protection, cooled to a certain temperature, and BCl was added dropwise under stirring. 3 (38.0mL,38.0mmol,4.0eq,1.0M in CH 2 Cl 2 ), after the addition was completed, the reaction system was stirred for 12 h at 0 ° C, and the reaction progress was tracked by thin layer chromatography until the raw material was consumed or no new progress was observed with time. The reaction solution was poured into ice water (200 mL), stirred, and extracted with dichloromethane (50 mL × 3). The organic phases were separated and combined, and saturated NaHCO 3 solution (50 mL × 3) and saturated NaCl solution (50 mL × 3), anhydrous MgSO 4 The mixture was dried and filtered, and the filtrate was concentrated under reduced pressure on a rotary evaporator. The residue was separated and purified by silica gel column chromatography (EtOAc / n-hexane = 1 / 1). The solid was purified by slurrying with n-hexane to obtain compound I. The white solid weighed 3.90 g after drying, with a yield of 76%.

[0053] Compound I was subjected to H NMR spectrum test, and the results were as follows:

[0054] 1 H NMR (DMSO-d 6,400MHz), δ:7.40(d,1H,J=8.0Hz),7.21(d,1H,J=8.4Hz),7.24(d,1H,J=0.8Hz) ,7.01(d,2H,J=8.4Hz),6.86(d,2H,J=8.4Hz),5.32(t,1H,J=9.6Hz),5.04(m,1H) ,4.91(t,1H,J=9.6Hz),4.68(bs,1H),4.47(d,1H,J=9.6Hz),3.98-4.12(m,3H), 3.78-3.89(m,4H),2.00(s,3H),1.97(s,3H),1.92(s,3H),1.27(t,3H,J=7.0Hz).

[0055] Example 2

[0056] This example provides a series of preparation methods for 3-deoxydapagliflozin intermediate compounds, and explores the effects of tertiary amine type, tertiary amine dosage and reaction temperature on the yield of the product. The preparation method is referenced to Example 1, and its parameters are shown in Table 1.

[0057] Table 1

[0058]

[0059]

[0060] From the data in Table 1, it can be found that without adding chiral tertiary amine compounds, the compound I of the present invention cannot be obtained. Primary amines and secondary amines are not suitable as selective deacetylation reagents.

[0061] In addition, the reaction temperature of the present invention has a good yield when it is between -10°C and 20°C.

[0062] Furthermore, the chiral tertiary amine compound of the present invention has a good yield when the amount used is between 0.5 eq and 1.0 eq.

[0063] Example 3

[0064] This example provides a method for preparing 3-deoxydapagliflozin, and the specific steps and reaction equations are as follows:

[0065]

[0066] S1. Add iodine (3.67 g, 14.44 mmol) to dry toluene (100 mL), protect with nitrogen, stir under ice-water bath cooling, add triphenylphosphine (3.79 g, 14.44 mmol) in batches, continue stirring at this temperature for half an hour after addition, and then add imidazole (1.97 g, 28.88 mmol) in batches, continue stirring at this temperature for half an hour after addition, add compound I (3.90 g, 7.22 mmol) to the above system, heat and reflux for 2 hours, and TLC detection shows that the reaction is complete. After the reaction solution is cooled to room temperature, pour it into ice water (200 mL), stir for 5 minutes and separate to obtain the organic phase, extract the aqueous phase with dichloromethane (100 mL × 3), combine the organic phases, wash with saturated sodium thiosulfate solution (50 mL × 3) and saturated NaCl solution (50 mL × 3) in turn, and anhydrous MgSO 4 The desiccant was removed by suction filtration, and the filtrate was concentrated under reduced pressure on a rotary evaporator. The residue was subjected to silica gel column chromatography (EtOAc / n-hexane = 1 / 10) to obtain compound 2. A white foamy solid weighed 3.77 g after drying, with a yield of 81%.

[0067] The test data are as follows:

[0068] 1 H NMR (DMSO-d 6 ,400MHz)δ:7.43(d,1H,J=8.0Hz),7.36(d,1H,J=2.0Hz),7.31(dd,1H,J=1.8Hz,8.2Hz),7.08(d,2H,J=8.4Hz),6.83(d, 2H,J=8.4Hz),5.21(t,1H,J=3.8Hz),4.63(d,1H,J=9.2Hz),4.32-4.41(m,2H),4.22-4.26(m,1H),4.16(dd,1H,J=5.2Hz and 12.4Hz),4.05-4.10(m,1H),3.94-4.00(m,4H),2.09(s,3H),2.03(s,3H),1.79(s,3H),1.27(t,3H,J=7.0Hz).

[0069] S2. Compound 2 (3.77 g, 5.85 mmol) was dissolved in MeOH (30 mL) and THF (10 mL), and Et3N (2.43 mL, 17.54 mmol) and 10% Pd / C (0.38 g) were added. Catalytic hydrogenation reduction was carried out at room temperature according to the standard procedure, and the mixture was stirred overnight. The reaction was complete when detected by TLC. The reaction solution was filtered to remove the solid, and the filtrate was concentrated and evaporated under reduced pressure on a rotary evaporator. The residue was diluted with water (100 mL), extracted with dichloromethane (50 mL × 3), and the organic phases were combined, washed with saturated NaCl solution (50 mL × 3), and anhydrous MgSO 4 After drying, the desiccant was removed by suction filtration, and the filtrate was concentrated under reduced pressure on a rotary evaporator. The residue was chromatographed on a silica gel column (EtOAc / n-hexane = 1 / 10) to obtain compound 3. The white solid weighed 2.58 g after drying, with a yield of 85%.

[0070] The test data are as follows:

[0071] Mp=83℃-84℃. 1 H NMR (DMSO-d 6 ,400MHz), δ:7.42(d,1H,J=8.4Hz),7.20-7.24(m,

[0072] 2H),7.07(d,2H,J=8.4Hz),6.84(d,2H,J=8.4Hz),4.74-4.83(m,1H),4.67-4.74(m,1H),4.44(d,1H,J=9.6Hz),4.04-4.17(m,2H),3.93- 4.02(m,4H),3.37-3.89(m,1H),2.44-2.48(m,1H),2.03(s,3H),2.01(s,3H),1.76(q,1H,J=11.3Hz),1.75(s,3H),1.27(t,3H,J=6.8Hz).

[0073] S3, compound 3 (2.85 g, 5.49 mmol) were dissolved in MeOH (30 mL), heated to 50 ° C, and 30% NaOH solution (5.5 mL) was slowly added. After the addition was completed, the reaction mixture was heated to reflux for 30 min. TLC detected that the reaction was complete. After the reaction solution was cooled, it was poured into ice water (100 mL), adjusted to pH = 8 with concentrated hydrochloric acid, extracted with dichloromethane (50 mL × 3), combined the organic phases, washed with saturated brine (50 mL × 3), anhydrous MgSO 4After drying, the desiccant was removed by suction filtration, and the solvent was evaporated on a rotary evaporator. The residue was subjected to column chromatography (EtOAc / n-hexane = 1 / 10) to obtain 3-deoxydapagliflozin as a white foam solid, which weighed 2.11 g after drying, with a yield of 98%.

[0074] The test data are as follows:

[0075] 1 H NMR (DMSO-d 6 ,400MHz)δ:7.36(d,J=8.4Hz,1H),7.32(d,J=1.8Hz,1H),7.23(dd,J=1.8Hz and 8.4Hz,1H),7.10(d,J=8.8Hz,2H),6.81(d,J=8.4Hz,2H),4.83(d,J=5.6Hz,1H),4.75(d,J=6.4Hz,1H),4.38(t,J=5.8Hz,1H),3.90-4.03(m,4H), 3.86(d,J=9.0Hz,1H),3.65-3.70(m,1H),3.24-3.47(m,3H),3.06-3.11( m, 1H), 2.21-2.26 (m, 1H), 1.44 (q, J = 11.5Hz, 1H), 1.27 (t, J = 6.8Hz, 3H).

[0076] In summary, the present invention uses compound 1 as a starting material and obtains 3-deoxydapagliflozin through four-step synthesis, and the total yield of the four steps is 76%*81%*85%*98%*100%=51.28%.

[0077] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge scope of ordinary technicians in the relevant technical field without departing from the purpose of the present invention.

Claims

1. A 3-deoxydapagliflozin intermediate compound, characterized in that: It has the structure shown in Formula I:

2. A method for preparing the 3-deoxydapagliflozin intermediate compound according to claim 1, characterized in that: The steps include: Compound 1, an organic solvent, boron trichloride and a chiral tertiary amine are mixed and reacted to obtain; Wherein, the structural formula of compound 1 is as follows: The molar ratio of the compound 1 to the chiral tertiary amine is 1:(0.1-1); the reaction temperature is -10°C to 20°C; The chiral tertiary amine is selected from at least one of the following structural formulas:

3. The preparation method according to claim 2, characterized in that: The organic solvent is selected from at least one of dichloromethane, chloroform or carbon tetrachloride.

4. Use of the 3-deoxydapagliflozin intermediate compound according to claim 1 for preparing 3-deoxydapagliflozin.

5. A method for preparing 3-deoxydapagliflozin, characterized in that: The steps include: S1. subjecting the 3-deoxydapagliflozin intermediate compound of claim 1 to iodination reaction to obtain compound 2; S2, removing iodine from compound 2 under the action of a reducing agent to obtain compound 3; S3, hydrolyzing compound 3 under alkaline conditions to remove the acetyl group to obtain 3-deoxydapagliflozin; Among them, the structural formulas of compound 2, compound 3 and 3-deoxydapagliflozin are as follows:

6. The method for preparing 3-deoxydapagliflozin according to claim 5, characterized in that: The base used in the alkaline condition is at least one selected from sodium hydroxide, sodium ethoxide, sodium methoxide, potassium hydroxide or lithium hydroxide.

7. The method for preparing 3-deoxydapagliflozin according to claim 5, characterized in that: The reducing agent includes hydrogen or tri-n-butyltin hydride.

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