Preparation method of diacerein impurity

Abstract

The invention discloses a diacerein impurity preparation method, which comprises: S1, mixing rhein, a catalyst, acetic anhydride and a solvent, stirring to dissolve, carrying out a stirring reaction at a room temperature, adding dichloromethane and an ammonium chloride saturated solution after the reaction is completed, carrying out liquid separation, and carrying out rotary evaporation on the organic phase to obtain an intermediate; and S2, uniformly mixing the intermediate obtained in the step S1 and tetrahydrofuran, stirring in an ice-water bath for 0.5-1 hour, then dropwise adding a borane tetrahydrofuran complex under the protection of nitrogen, reacting in the ice-water bath after dropwise adding is completed, transferring to room temperature after the reaction is completed, continuously carrying out constant-temperature reaction, adding dichloromethane and purified water after the reaction is completed, carrying out liquid separation, and drying an organic phase, so as to obtain the borane tetrahydrofuran catalyst. And carrying out silica gel column chromatography and recrystallization to obtain the diacerein impurity. The diacerein impurity is creatively synthesized for the first time, and the diacerein impurity prepared by the method has the advantages of few byproducts, high product purity and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical pharmaceutical synthesis, and particularly relates to a method for preparing diacerein impurities. Background Art

[0002] Diacerein, chemically named 4,5-di(acetoxy)-9,10-dihydro-9,10-dioxo-2-anthracenecarboxylic acid, is a drug for treating osteoarthritis produced by Argentina TRB Pharma SA, with the trade name of Ambidin. Diacerein is an interleukin (IL-1) inhibitor, which exerts anti-inflammatory and protective effects on articular cartilage by inhibiting the activity of metalloproteinases and stabilizing lysosomal membranes. It is mainly used in the treatment of osteoarthritis clinically, and can significantly relieve the symptoms of osteoarthritis (AO) and effectively correct the structure. It is a slow-acting drug that changes the symptoms and condition of osteoarthritis.

[0003] There are many reports on the preparation methods of diacerein, mainly in two ways: total synthesis method and semi-synthesis method: (1) Total synthesis method, Steve Tisserand et al. used m-tribromobenzene and o-methoxybenzoic acid as main raw materials, and prepared diacerein through eight steps of substitution, Friedel-Crafts reaction, condensation, hydrolysis, protection group removal, acetylation, etc. (2) Semi-synthesis method, most of them use anthraquinone natural products as raw materials, and change their structures to obtain diacerein. This type of method often uses aloe-emodin as the starting material, and obtains diacerein through oxidation and acetylation. For example, in the US patent application with publication number US5652265 and the Chinese patent with authorization number CN200610049171.9, it is disclosed that aloe-emodin and acetic anhydride are reacted with a catalyst to acetylate all hydroxyl groups, and the acetylated intermediate is oxidized with Jones reagent to oxidize the hydroxyl groups to obtain diacerein. The crude diacerein is obtained by the above-mentioned synthesis method, and then subjected to purification methods such as recrystallization, solvent removal, and heavy metal removal to obtain a final product that meets the pharmacopoeia standards.

[0004] In the synthesis of diacerein, a variety of impurities are inevitably generated. For example, the impurities of diacerein in the European Pharmacopoeia mainly include aloe-emodin, rhein, monoacetyl rhein, triacetyl aloe-emodin, acetyl aloe-emodin, etc., and as for the diacetyl aloe-emodin impurity in diacerein, the synthesis process of the impurity has not been reported in the existing literature. The present invention innovatively proposes a method for efficiently synthesizing the impurity, which provides a basis for the synthesis method of the diacerein impurity. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing diacerein impurities.

[0006] To achieve the above object, the present invention provides the following technical solutions:

[0007] A method for preparing diacerein impurities comprises the following steps:

[0008] S1, mixing rhein, a catalyst, acetic anhydride and a solvent, stirring to dissolve, stirring to react at room temperature, adding dichloromethane and a saturated ammonium chloride solution after the reaction, separating the liquids, and rotary evaporating the organic phase to obtain an intermediate;

[0009] S2, the intermediate of step S1 and tetrahydrofuran are mixed uniformly, stirred in an ice-water bath for 0.5-1h, and then borane tetrahydrofuran complex is added dropwise under nitrogen protection, and reacted in an ice-water bath after the addition is completed. After the reaction is completed, the mixture is transferred to room temperature and the isothermal reaction is continued. After the reaction is completed, dichloromethane and purified water are added, and the liquids are separated. The organic phase is dried, and after silica gel column chromatography and recrystallization, the diacerein impurity is obtained.

[0010] Preferably, the molar ratio of rhein to acetic anhydride in step S1 is 2-5:10-20.

[0011] More preferably, the molar ratio of rhein to acetic anhydride in step S1 can be 2:10, 3:10, 4:10, 5:10, 2:15, 3:15, 4:15, 5:15, 4:20, 5:20, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0012] Preferably, the stirring reaction in step S1 is carried out at a temperature of 22-28° C. and for a time of 10-15 h.

[0013] More preferably, the temperature of the stirring reaction in step S1 can be 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, or 28°C, and the time can be 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, or 15h, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0014] Preferably, the catalyst in step S1 is 4-dimethylaminopyridine.

[0015] Preferably, the solvent in step S1 is dichloromethane.

[0016] Preferably, the reaction time in the ice water bath in step S2 is 1-2 h.

[0017] More preferably, the reaction time in the ice water bath in step S2 can be 60 min, 70 min, 80 min, 90 min, 100 min, 1100 min, 120 min, but is not limited to the listed values, and other values ​​not listed within the numerical range are also applicable.

[0018] Preferably, the temperature of the isothermal reaction in step S2 is 22-28° C. and the time is 10-15 h.

[0019] More preferably, the temperature of the isothermal reaction in step S2 can be 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, or 28°C, and the time can be 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, or 15h, but is not limited to the listed values, and other values ​​not listed within the numerical range are equally applicable.

[0020] Preferably, in step S2, the mass ratio of the intermediate to the tetrahydrofuran borane complex solution is 5-10:50-100, and the concentration of borane in the borane tetrahydrofuran complex is 1 mol / L.

[0021] Preferably, the structural formula of the diacerein impurity described in step S2 is as follows:

[0022]

[0023] Preferably, the eluent for the silica gel column chromatography in step S2 is a mixture of petroleum ether:ethyl acetate:glacial acetic acid in a volume ratio of 20:10:1, and recrystallization is performed with anhydrous ethanol after chromatography.

[0024] The reaction process diagram of the synthetic diacerein impurities of the present invention is as follows:

[0025]

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] (1) The present invention creatively synthesized diacerein impurity diacetyl aloe-emodin for the first time.

[0028] (2) The present invention creatively uses rhein and acetic anhydride as raw materials, dichloromethane as solvent, and 4-dimethylaminopyridine as catalyst to first react and synthesize an intermediate at room temperature, and then uses tetrahydrofuran as solvent to react the intermediate with a borane tetrahydrofuran complex in an ice-water bath. After the reaction is completed, the reaction is returned to room temperature, and then liquid separation and purification are performed to obtain diacerein impurities. The pure product is a light yellow solid powder. The diacerein impurities prepared by this method have the advantages of less product by-products and high product purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the HPLC spectrum of Example 1 of the present invention, from which it can be seen that the liquid phase purity of the product is 98.22%.

[0030] Figure 2 It is the mass spectrum of the diacerein impurity of Example 1 of the present invention.

[0031] Figure 3 The figure is the H NMR spectrum of the diacerein impurity of Example 1 of the present invention. DETAILED DESCRIPTION

[0032] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] In the present invention, rhein (Shanghai BiDe Pharmaceutical Technology Co., Ltd., 98%, DMV450); 4-dimethylaminopyridine (Shanghai Yien Chemical Technology Co., Ltd., 99%, R004061); borane tetrahydrofuran complex was purchased from Shanghai Hansi Chemical Co., Ltd., with a concentration of 1 mol / L.

[0034] Example 1

[0035] A method for preparing diacerein impurities comprises the following steps:

[0036] S1, 0.568g (2mmol) of rhein, 48.9mg (0.4mmol) of 4-dimethylaminopyridine, 1.02g (10mmol) of acetic anhydride, and 10mL of dichloromethane were mixed, stirred to dissolve, and stirred to react at room temperature (25°C) for 12h. After the reaction was completed, 30mL of dichloromethane and 30mL of saturated ammonium chloride solution were added, mixed evenly, allowed to stand for stratification, separated, and the organic phase was rotary evaporated to obtain 0.6g of the intermediate (yield 81.5%);

[0037] S2, 0.6g intermediate of step S1 and 20mL tetrahydrofuran were mixed uniformly, stirred in an ice-water bath for 0.5h, then 6mL borane tetrahydrofuran complex (1mol / L) was added dropwise under nitrogen protection, reacted in an ice-water bath for 1h, and after the reaction was completed, the mixture was transferred to room temperature (25°C) and continued to react at a constant temperature for 12h. After the reaction was completed, 30mL dichloromethane and 30mL purified water were added, mixed uniformly and allowed to stand for stratification, separated, the organic phase was dried, and subjected to silica gel column chromatography, eluent being: a mixed solution of petroleum ether: ethyl acetate: glacial acetic acid in a volume ratio of 20:10:1, and then recrystallized from anhydrous ethanol to obtain 0.39g of the diacerein impurity (purity of 98.22%, yield of 67%).

[0038] 1H NMR (600MHz, DMSO-d6) δ8.14(dd,J=7.8,1.3Hz,1H),8.10(dt,J=1.7,0.8Hz,1H),7.93(t,J=7.9Hz,1H),7.63(dd,J=8 .0,1.3Hz,1H),7.53(dd,J=1.7,0.9Hz,1H),5.66(t,J=5.8Hz,1H),4.69(dt,J=5.9,0.9Hz,2H),2.39(d,J=1.2Hz,6H).

[0039] ESI m / z:355.1[M+H] + ,372.1[M+Na] + .

[0040] Example 2

[0041] A method for preparing diacerein impurities comprises the following steps:

[0042] S1, 1.136g (4mmol) of rhein, 48.9mg (0.4mmol) of 4-dimethylaminopyridine, 2.04g (20mmol) of acetic anhydride, and 20mL of dichloromethane were mixed, stirred to dissolve, and stirred to react at room temperature (22°C) for 15h. After the reaction was completed, 50mL of dichloromethane and 50mL of saturated ammonium chloride solution were added, mixed evenly, allowed to stand for stratification, separated, and the organic phase was rotary evaporated to obtain 1.15g of the intermediate (yield 76.7%);

[0043] S2, 1.15g intermediate of step S1 and 40mL tetrahydrofuran were mixed uniformly, stirred in an ice-water bath for 0.5h, then 6mL borane tetrahydrofuran complex (1mol / L) was added dropwise under nitrogen protection, reacted in an ice-water bath for 1.5h, and after the reaction was completed, the mixture was transferred to room temperature (22°C) and continued to react at a constant temperature for 15h. After the reaction was completed, 50mL dichloromethane and 50mL purified water were added, mixed uniformly and allowed to stand for stratification, separated, the organic phase was dried, and subjected to silica gel column chromatography, eluent being: a mixed solution of petroleum ether: ethyl acetate: glacial acetic acid in a volume ratio of 20:10:1, and then recrystallized from anhydrous ethanol to obtain 0.69g of the diacerein impurity (purity of 97.65%, yield of 63.9%).

[0044] Example 3

[0045] A method for preparing diacerein impurities comprises the following steps:

[0046] S1, 0.852g (3mmol) of rhein, 48.9mg (0.4mmol) of 4-dimethylaminopyridine, 1.53g (15mmol) of acetic anhydride, and 20mL of dichloromethane were mixed, stirred to dissolve, and stirred to react at room temperature (28°C) for 10h. After the reaction was completed, 40mL of dichloromethane and 40mL of saturated ammonium chloride solution were added, mixed evenly, allowed to stand for stratification, separated, and the organic phase was rotary evaporated to obtain 0.89g of the intermediate (yield 79.1%);

[0047] S2, 0.89g intermediate of step S1 and 30mL tetrahydrofuran were mixed uniformly, stirred in an ice-water bath for 1h, then 6mL borane tetrahydrofuran complex (1mol / L) was added dropwise under nitrogen protection, reacted in an ice-water bath for 2h after the addition was completed, and the reaction was continued at room temperature (28°C) for 10h after the reaction was completed. After the reaction was completed, 40mL dichloromethane and 40mL purified water were added, mixed uniformly and allowed to stand for stratification, separated, the organic phase was dried, and subjected to silica gel column chromatography, the eluent was a mixed solution of petroleum ether: ethyl acetate: glacial acetic acid in a volume ratio of 20:10:1, and then recrystallized from anhydrous ethanol to obtain 0.58g of the diacerein impurity (purity of 96.31%, yield of 69.4%).

[0048] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing diacerein impurities, characterized in that, The following steps are involved: S1, mixing rhein, a catalyst, acetic anhydride and a solvent, stirring to dissolve, stirring to react at room temperature, adding dichloromethane and a saturated ammonium chloride solution after the reaction, separating the liquids, and rotary evaporating the organic phase to obtain an intermediate; S2, the intermediate of step S1 and tetrahydrofuran are mixed uniformly, stirred in an ice-water bath for 0.5-1h, and then borane tetrahydrofuran complex is added dropwise under nitrogen protection, and reacted in an ice-water bath after the addition is completed. After the reaction is completed, the mixture is transferred to room temperature and the isothermal reaction is continued. After the reaction is completed, dichloromethane and purified water are added, and the liquids are separated. The organic phase is dried, and after silica gel column chromatography and recrystallization, the diacerein impurity is obtained.

2. The preparation method according to claim 1, characterized in that: The molar ratio of rhein to acetic anhydride in step S1 is 2-5:10-20.

3. The preparation method according to claim 1, characterized in that: The stirring reaction in step S1 is carried out at a temperature of 22-28° C. for 10-15 hours.

4. The preparation method according to claim 1, characterized in that: The catalyst in step S1 is 4-dimethylaminopyridine.

5. The preparation method according to claim 1, characterized in that: The solvent in step S1 is dichloromethane.

6. The preparation method according to claim 1, characterized in that: The reaction time in the ice water bath in step S2 is 1-2 h.

7. The preparation method according to claim 1, characterized in that: The isothermal reaction in step S2 is carried out at a temperature of 22-28° C. and for a time of 10-15 hours.

8. The preparation method according to claim 1, characterized in that: The mass ratio of the intermediate to the tetrahydrofuran borane complex solution in step S2 is 5-10:50-100, and the concentration of borane in the borane tetrahydrofuran complex is 1 mol / L.

9. The preparation method according to claim 1, characterized in that: The structural formula of the diacerein impurity described in step S2 is as follows:

10. The preparation method according to claim 1, characterized in that: The eluent for the silica gel column chromatography in step S2 is a mixture of petroleum ether:ethyl acetate:glacial acetic acid in a volume ratio of 20:10:1, and recrystallization is performed with anhydrous ethanol after chromatography.

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