Preparation method of rosuvac intermediate

Abstract

The invention discloses a preparation method of a rosuvac intermediate, and belongs to the technical field of medicine synthesis. The preparation method of the rosuvavar intermediate comprises the following steps: S1, mixing an intermediate D4, organic alkali, methyl mercaptothiadiazole, DMF (Dimethyl Formamide) and an aluminum salt catalyst, heating to 95-125 DEG C, carrying out a first heat preservation reaction, carrying out phase separation, and adding dichloromethane for reverse extraction to obtain a dichloromethane solution of an intermediate D4-1; the molar yield of the intermediate D4-1 can reach 97% or above.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a rosuvastatin intermediate. Background Art

[0002] In the synthesis process of Rosuvastatin, intermediates D4-1 and D4-2 are required. However, in the synthesis route of intermediate D4-2, sodium carbonate is usually used as an acidifying agent, and water is produced during the reaction. The production of water is not conducive to the forward reaction and affects the yield of the intermediate. The yield of the intermediate will affect the yield of the final product Rosuvastatin.

[0003] The structural formula of intermediate D-1 is

[0004]

[0005] The structural formula of intermediate D-2 is

[0006]

[0007] How to improve the yield of intermediates is a technical problem that needs to be solved in the prior art. Summary of the invention

[0008] The purpose of the present invention is to overcome the above technical deficiencies, provide a method for preparing a rosuvastatin intermediate, and solve the technical problem of how to improve the yield of the intermediate in the prior art.

[0009] In order to achieve the above technical purpose, the technical solution of the present invention provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0010] S1, mixing the intermediate D4, an organic base, methylthiothiadiazole, DMF and an aluminum salt catalyst, then heating to 95-125° C. for a first heat preservation reaction, then phase separation, and then adding dichloromethane for stripping to obtain a dichloromethane solution of the intermediate D4-1;

[0011] The structural formula of the intermediate D4 is:

[0012]

[0013] The structural formula of the intermediate D4-1 is:

[0014]

[0015] In any implementation manner, after step S1, the method further includes:

[0016] S2, mixing the dichloromethane solution of the intermediate D4-1, ammonium heptamolybdate and tetrabutylammonium bromide, adding hydrogen peroxide dropwise at 25-35° C., and then performing a second heat preservation reaction to obtain the intermediate D4-2;

[0017] The structural formula of the intermediate D4-2 is:

[0018]

[0019] In any embodiment, the first insulation reaction time is 5-8 hours.

[0020] In any embodiment, the organic base is one or both of triethylamine and tri-n-propylamine.

[0021] In any embodiment, the aluminum salt catalyst is one or both of aluminum trichloride and aluminum hydroxide.

[0022] In any embodiment, the mass ratio of the intermediate D4 to the organic base is 5:(2-3); and / or, the mass ratio of the intermediate D4 to the methylmercaptothiadiazole is 5:(2-3); and / or, the mass ratio of the intermediate D4 to the DMF is 25:(6-8); and / or, the mass ratio of the intermediate D4 to the aluminum salt catalyst is 50:(1-2).

[0023] In any embodiment, in step S1, the phase separation includes: cooling after the first heat preservation reaction, then adding dichloromethane and water for stirring and extraction, transferring the materials and separating the liquids, collecting the organic phase for later use, and back-extracting the aqueous phase with dichloromethane to obtain a dichloromethane solution of the intermediate D4-1.

[0024] In any embodiment, in step S2, the second insulation reaction time is more than 12 hours.

[0025] In any embodiment, in step S2, after the second insulation reaction, it also includes: transferring materials and separating liquids, collecting the oil phase, stripping the aqueous phase with dichloromethane, combining the organic phases, dropping a sodium thiosulfate aqueous solution for quenching and washing, controlling the temperature during the dropping process at 15 to 45°C, then transferring the materials and separating the layers, reducing the pressure on the lower organic phase to recover the solvent, adding methanol to the concentrate and heating to dissolve, reflux and heat preservation, and then cooling and crystallizing to obtain the intermediate D4-2.

[0026] In any embodiment, in step S2, the mass ratio of the added ammonium heptamolybdate to the intermediate D4 is (1-2):50; and / or, the mass ratio of the added tetrabutylammonium bromide to the intermediate D4 is (2-3):50.

[0027] Compared with the prior art, the beneficial effects of the present invention include: the preparation method of the rosuvastatin intermediate proposed by the present invention comprises the following steps: S1, mixing the intermediate D4, an organic base, methylmercaptothiadiazole, DMF and an aluminum salt catalyst, then heating to 95-125° C. for a first heat preservation reaction, then phase separation, and then adding dichloromethane for stripping to obtain a dichloromethane solution of the intermediate D4-1. In the reaction, the organic base is used as an acidifying agent to avoid the generation of water during the reaction, thereby facilitating the forward reaction. Moreover, the addition of the aluminum salt catalyst can promote the complete conversion of the raw materials, and greatly improve the product yield. The molar yield of the intermediate D4-1 can be as high as 97% or more. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is a high performance liquid chromatogram of the intermediate D4-2 of Example 1 of the present invention. DETAILED DESCRIPTION

[0029] The "range" disclosed in the present application is defined in the form of a lower limit and an upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundaries of the particular range. The range defined in this way can be inclusive or exclusive of the end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a range. For example, if a range of 60 to 120 and 80 to 110 is listed for a particular parameter, it is understood that a range of 60 to 110 and 80 to 120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following ranges can all be expected: 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4 and 2 to 5. In the present application, unless otherwise specified, the numerical range "a to b" represents an abbreviation of any real number combination between a and b, where a and b are both real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0030] If there is no special explanation, the "include" and "comprising" mentioned in this application are open-ended or closed-ended. For example, the "include" and "comprising" may mean that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0031] If not specifically stated, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0032] This specific embodiment provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0033] S1. Mix the intermediate D4, an organic base, methylmercaptothiadiazole, DMF and an aluminum salt catalyst, then heat to 95-125°C for the first heat preservation reaction for 5-8 hours, then separate the phases, and then add dichloromethane for stripping to obtain a dichloromethane solution of the intermediate D4-1; the organic base is one or both of triethylamine and tri-n-propylamine; the aluminum salt catalyst is one or both of aluminum trichloride and aluminum hydroxide; the mass ratio of the intermediate D4 to the organic base is 5:(2 -3); the mass ratio of the intermediate D4 to the methylmercaptothiadiazole is 5:(2-3); the mass ratio of the intermediate D4 to the DMF is 25:(6-8); the mass ratio of the intermediate D4 to the aluminum salt catalyst is 50:(1-2); the phase separation comprises: cooling after the first heat preservation reaction, then adding dichloromethane and water for extraction, transferring the material and separating the liquids, collecting the organic phase for standby use, and stripping the aqueous phase with dichloromethane to obtain a dichloromethane solution of the intermediate D4-1;

[0034] The structural formula of the intermediate D4 is:

[0035]

[0036] The structural formula of the intermediate D4-1 is:

[0037]

[0038] In some embodiments, after step S1, the method further comprises: S2, mixing a dichloromethane solution of the intermediate D4-1, ammonium heptamolybdate and tetrabutylammonium bromide, adding hydrogen peroxide dropwise at 25-35° C., and then performing a second heat preservation reaction for more than 12 hours, transferring the materials and separating the liquids, collecting the oil phase, stripping the aqueous phase with dichloromethane, combining the organic phases, dropping a sodium thiosulfate aqueous solution for quenching and washing, controlling the temperature during the dropping process at 15-45° C., and then transferring the materials and separating the layers, reducing the pressure on the lower organic phase to recover the solvent, adding methanol to the concentrate and heating to dissolve, reflux and heat preservation, and then cooling and crystallizing to obtain the intermediate D4-2; the mass ratio of the added ammonium heptamolybdate to the intermediate D4 is (1-2):50, and the mass ratio of the added tetrabutylammonium bromide to the intermediate D4 is (2-3):50;

[0039] The structural formula of the intermediate D4-2 is:

[0040]

[0041] The reaction formula is as follows:

[0042]

[0043] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0044] In the present invention, reference is made to “some embodiments”, “this embodiment”, examples, etc., which describe a subset of all possible embodiments, but it can be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0045] If similar descriptions of "first / second" appear in the application documents, the following instructions are added. In the following description, the terms "first\second\third" involved are merely used to distinguish similar objects and do not represent a specific ordering of the objects. It can be understood that "first\second\third" can be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0046] In this embodiment, the term "and / or" is merely a description of the association relationship between associated objects, indicating that three relationships may exist. For example, object A and / or object B may represent three situations: object A exists alone, object A and object B exist at the same time, and object B exists alone.

[0047] Hereinafter, the embodiments of the present application will be described. The embodiments described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. If no specific techniques or conditions are indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0048] Example 1

[0049] This embodiment provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0050] S1, add 50g of intermediate D4, 27g of tri-n-propylamine, 20.16g of methylmercaptothiadiazole, 12g of DMF, and 1g of aluminum trichloride, stir and disperse for 5min, heat to react, control the temperature at 95-100℃ and keep the reaction for 5h, take a sample plate until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150ml of dichloromethane and 100ml of water, stir and extract for 0.5h, transfer and separate, collect the organic phase for later use, and extract the aqueous phase once with 50ml of dichloromethane to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 97.5%;

[0051] S2, add 1g ammonium heptamolybdate and 2g tetrabutylammonium bromide to the D4-1 dichloromethane solution, stir and disperse, control the temperature at 30-35℃, and add 180g 30% hydrogen peroxide reaction (dropping time 1.5 ~ 2h), after the dropwise addition, keep warm and react for 12h until the raw material is completely converted, shut down the reaction, transfer the material and separate the liquid, collect the oil phase, the aqueous phase is stripped once with 50ml of dichloromethane, the organic phase is combined, and 100g of a 2% sodium thiosulfate aqueous solution is added dropwise for quenching and washing. The dropping time is 15 minutes, and the temperature is controlled at 15-45°C during the dropping process. After the dropwise addition is completed, stir for 15 minutes, transfer the material and separate the layers, discard the upper aqueous phase, and reduce the pressure on the lower organic phase to recover the solvent until there is no flow. 90ml of methanol is added to the concentrate and the temperature is raised to dissolve, reflux and keep warm for 0.5h, cool and crystallize, control the temperature at 0-5°C and keep warm for 2h, filter, rinse the filter cake with 10g*2 frozen methanol to obtain D4-2 wet product, and dry it in a 45°C forced air oven to constant weight to obtain the intermediate D4-2 finished product. The molar yield of intermediate D4-2 is 92.5%, and the purity of intermediate D4-2 is 99.5%. Combination Figure 1 It can also be further said that the intermediate D4-2 obtained has high purity.

[0052] Example 2

[0053] This embodiment provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0054] S1, add 50g of intermediate D4, 25g of triethylamine, 26g of methylmercaptothiadiazole, 14g of DMF, and 1g of aluminum trichloride, stir and disperse for 5min, heat to react, control the temperature at 110-115℃ and keep the reaction for 6h, take a sample until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150ml of dichloromethane and 100ml of water, stir and extract for 0.5h, transfer and separate, collect the organic phase for later use, and extract the aqueous phase once with 50ml of dichloromethane to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 96.2%;

[0055] S2, add 1.5g ammonium heptamolybdate and 2.5g tetrabutylammonium bromide to the D4-1 dichloromethane solution, stir and disperse, control the temperature at 25-30℃, and add 180g 30% hydrogen peroxide reaction (dropping time 1.5h), after the dropwise addition, keep warm and react for 14h until the raw material is completely converted, shut down the reaction, transfer the material and separate the liquid, collect the oil phase, extract the aqueous phase with 50ml dichloromethane once, combine the organic phases, add 100g of 2% sodium thiosulfate aqueous solution by mass concentration to quench and wash, the dropwise addition time is 15 minutes, the temperature is controlled at 15-45°C during the dropwise addition process, after the dropwise addition is completed, stir for 15 minutes, transfer the material and separate the layers, discard the upper aqueous phase, and reduce the pressure on the lower organic phase to recover the solvent until there is no flow, add 90ml methanol to the concentrate and heat to dissolve, reflux and keep warm for 0.5h, cool and crystallize, control the temperature at 0-5°C and keep warm for 2h, filter, rinse the filter cake with 10g*2 frozen methanol to obtain D4-2 wet product, dry it in a 45°C forced air oven to constant weight to obtain the intermediate D4-2 finished product, the molar yield of intermediate D4-1 is 93.2%, and the purity of intermediate D4-2 is 99.6%.

[0056] Example 3

[0057] This embodiment provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0058] S1, add 50g of intermediate D4, 30g of triethylamine, 20g of methylmercaptothiadiazole, 12g of DMF, and 1.5g of aluminum hydroxide, stir and disperse for 5min, heat to react, control the temperature at 120-125℃ and keep the reaction for 8h, take a sample until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150ml of dichloromethane and 100ml of water, stir and extract for 0.5h, transfer and separate, collect the organic phase for later use, and extract the aqueous phase with 50ml of dichloromethane once to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 96.6%;

[0059] S2, add 1g ammonium heptamolybdate and 2g tetrabutylammonium bromide to the D4-1 dichloromethane solution, stir and disperse, control the temperature at 30-35℃, and add 180g 30% hydrogen peroxide reaction (dropping time 2h), after the dropwise addition, keep the reaction warm for 15h until the raw material is completely converted, shut down the reaction, transfer the material and separate the liquid, collect the oil phase, extract the aqueous phase with 50ml dichloromethane once, combine the organic phases, add 100g of 2% sodium thiosulfate aqueous solution to quench and wash, the dropwise addition time is 15 minutes, the temperature is controlled at 15-45°C during the dropwise addition process, after the dropwise addition is completed, stir for 15 minutes, transfer the material and separate the layers, discard the upper aqueous phase, and reduce the pressure on the lower organic phase to recover the solvent until there is no flow, add 90ml methanol to the concentrate and heat it up to dissolve, reflux and keep warm for 0.5h, cool and crystallize, control the temperature at 0-5°C and keep warm for 2h, filter, rinse the filter cake with 10g*2 frozen methanol to obtain D4-2 wet product, dry it in a 45°C forced air oven to constant weight to obtain the intermediate D4-2 finished product, the molar yield of intermediate D4-1 is 92.7%, and the purity of intermediate D4-2 is 99.3%.

[0060] Example 4

[0061] This embodiment provides a method for preparing a rosuvastatin intermediate, comprising the following steps:

[0062] S1, add 50g of intermediate D4, 28g of tri-n-propylamine, 30g of methylmercaptothiadiazole, 16g of DMF, and 2g of aluminum hydroxide, stir and disperse for 5min, heat to react, control the temperature at 105-110℃ and keep the reaction for 7h, take a sample plate until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150ml of dichloromethane and 100ml of water, stir and extract for 0.5h, transfer and separate, collect the organic phase for later use, and extract the aqueous phase once with 50ml of dichloromethane to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 97.4%;

[0063] S2, add 1g ammonium heptamolybdate and 2g tetrabutylammonium bromide to the D4-1 dichloromethane solution, stir and disperse, control the temperature at 30-35℃, and add 180g 30% hydrogen peroxide reaction (dropping time 2h), after the dropwise addition, keep warm and react for 13h until the raw material is completely converted, shut down the reaction, transfer the material and separate the liquid, collect the oil phase, extract the aqueous phase with 50ml dichloromethane once, combine the organic phases, add 100g of 2% sodium thiosulfate aqueous solution by mass concentration to quench and wash, the dropwise addition time is 15 minutes, the temperature is controlled at 15-45°C during the dropwise addition process, after the dropwise addition is completed, stir for 15 minutes, transfer the material and separate the layers, discard the upper aqueous phase, and reduce the pressure on the lower organic phase to recover the solvent until there is no flow, add 90ml methanol to the concentrate and heat to dissolve, reflux and keep warm for 0.5h, cool and crystallize, control the temperature at 0-5°C and keep warm for 2h, filter, rinse the filter cake with 10g*2 frozen methanol to obtain D4-2 wet product, dry it in a 45°C forced air oven to constant weight to obtain the intermediate D4-2 finished product, the molar yield of intermediate D4-1 is 92.2%, and the purity of intermediate D4-2 is 99.2%.

[0064] Comparative Example 1

[0065] This comparative example proposes a method for preparing Rosuvastatin intermediate D4-1, comprising the following steps:

[0066] S1. Add 50 g of intermediate D4, 27 g of tri-n-propylamine, 20.16 g of methylmercaptothiadiazole, 12 g of DMF and 1 g of ferric chloride, stir and disperse for 5 min, heat to react, control the temperature at 95-100 °C and keep the reaction for 5 h, take a sample plate until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150 ml of dichloromethane and 100 ml of water, stir and extract for 0.5 h, transfer the material and separate the liquids, collect the organic phase for later use, and extract the aqueous phase once with 50 ml of dichloromethane to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 67.2%.

[0067] Comparative Example 2

[0068] This comparative example proposes a method for preparing Rosuvastatin intermediate D4-1, comprising the following steps:

[0069] S1. Add 50 g of intermediate D4, 27 g of tri-n-propylamine, 20.16 g of methylmercaptothiadiazole, 12 g of DMF and 1 g of trifluoromethanesulfonic acid, stir and disperse for 5 min, heat to react, control the temperature at 95-100 °C and keep the reaction for 5 h, take a sample plate until the methylmercaptothiadiazole raw material point disappears, shut down the reaction, cool down, add 150 ml of dichloromethane and 100 ml of water, stir and extract for 0.5 h, transfer and separate the materials, collect the organic phase for later use, and extract the aqueous phase once with 50 ml of dichloromethane to obtain a dichloromethane solution of intermediate D4-1; the molar yield of intermediate D4-1 is 52.7%.

[0070] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing a rosuvastatin intermediate, characterized in that: The following steps are involved: S1, mixing the intermediate D4, an organic base, methylthiothiadiazole, DMF and an aluminum salt catalyst, then heating to 95-125° C. for a first heat preservation reaction, then phase separation, and then adding dichloromethane for stripping to obtain a dichloromethane solution of the intermediate D4-1; The structural formula of the intermediate D4 is: The structural formula of the intermediate D4-1 is:

2. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: After step S1, the method further includes: S2, mixing the dichloromethane solution of the intermediate D4-1, ammonium heptamolybdate and tetrabutylammonium bromide, adding hydrogen peroxide dropwise at 25-35° C., and then performing a second heat preservation reaction to obtain the intermediate D4-2; The structural formula of the intermediate D4-2 is:

3. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: The first insulation reaction time is 5-8 hours.

4. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: The organic base is one or both of triethylamine and tri-n-propylamine.

5. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: The aluminum salt catalyst is one or both of aluminum trichloride and aluminum hydroxide.

6. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: The mass ratio of the intermediate D4 to the organic base is 5:(2-3); and / or, the mass ratio of the intermediate D4 to the methylmercaptothiadiazole is 5:(2-3); and / or, the mass ratio of the intermediate D4 to the DMF is 25:(6-8); and / or, the mass ratio of the intermediate D4 to the aluminum salt catalyst is 50:(1-2).

7. The method for preparing a Rosuva intermediate according to claim 1, characterized in that: In step S1, the phase separation includes: cooling after the first heat preservation reaction, then adding dichloromethane and water for stirring and extraction, transferring materials and separating liquids, collecting the organic phase for later use, and back-extracting the aqueous phase with dichloromethane to obtain a dichloromethane solution of the intermediate D4-1.

8. The method for preparing a Rosuva intermediate according to claim 2, characterized in that: In step S2, the second heat preservation reaction time is more than 12 hours.

9. The method for preparing a Rosuva intermediate according to claim 2, characterized in that: In step S2, after the second insulation reaction, it also includes: transferring materials and separating liquids, collecting the oil phase, stripping the aqueous phase with dichloromethane, combining the organic phases, dropping a sodium thiosulfate aqueous solution for quenching and washing, controlling the temperature during the dropping process at 15 to 45°C, then transferring the materials and separating the layers, reducing the pressure on the lower organic phase to recover the solvent, adding methanol to the concentrate and heating to dissolve, reflux and heat preservation, and then cooling and crystallizing to obtain the intermediate D4-2.

10. The method for preparing a Rosuva intermediate according to claim 2, characterized in that: In step S2, the mass ratio of the added ammonium heptamolybdate to the intermediate D4 is (1-2):50; and / or the mass ratio of the added tetrabutylammonium bromide to the intermediate D4 is (2-3):50.

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