A process for the preparation of a rosuvastatin calcium intermediate

Abstract

The application relates to the technical field of medical intermediates, in particular to a preparation method of a rosuvastatin calcium intermediate, wherein the rosuvastatin calcium intermediate is a synthetic route of or wherein R represents C1-C3 alkyl, and X and Y represent halogen. The preparation method effectively solves the problems of complicated steps and high cost in the existing synthetic route; meanwhile, the whole synthetic route has the advantages of mild reaction condition, convenient operation, high yield and suitability for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediates, specifically to a method for preparing rosuvastatin calcium intermediate. Background Technology

[0002] Rosuvastatin calcium (CAS: 147098-20-2) is an anti-hyperlipidemia drug, belonging to the HMG-CoA reductase inhibitor class. Developed by AstraZeneca in the UK, it is indicated for the treatment of various lipid abnormalities, including hypercholesterolemia, mixed lipid dyslipidemia, and isolated hypertriglyceridemia. Rosuvastatin calcium is currently the most potent and comprehensive statin drug on the market, exhibiting better lipid-lowering effects and higher HDL cholesterol levels than atorvastatin, which is widely considered the most effective statin. It also has better tolerability, fewer side effects, and unique pharmacokinetic characteristics, with a half-life of approximately 20 hours, requiring only once-daily dosing. Rosuvastatin calcium is currently marketed as a hemicalcium salt.

[0003] This is an important intermediate for rosuvastatin calcium. Patent CN1738789 describes a method for preparing this rosuvastatin calcium intermediate, and its synthetic route is as follows:

[0004]

[0005] The silicon-based protective reagents used in this route are expensive, and the process generates silicon-containing waste that is difficult to treat, resulting in significant environmental pressure, high costs, and hindering industrial production. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing rosuvastatin calcium intermediates that has a simple overall synthetic route, is easy to operate, has high yield and purity, and is suitable for large-scale industrial production.

[0007] To achieve the above objectives, the present invention provides the following technical solution:

[0008] A method for preparing a rosuvastatin calcium intermediate, wherein the rosuvastatin calcium intermediate is... Its synthetic route is as follows:

[0009]

[0010] In this context, R represents a C1 to C3 alkyl group, and X and Y represent halogens.

[0011] Specifically, the following steps are included:

[0012] (1) Compound 4 was protected by a hydroxyl group to prepare compound 3 or compound 3';

[0013] (2) Compound 3 or 3' is deprotected after docking with compound 2 to prepare the compound.

[0014] Further, in step (1), compound 4 is esterified with an anhydride to prepare compound 3, and a base is used as an acid-binding agent. The molar ratio of compound 4, anhydride and base is 1:1 to 1.2:1 to 1.2.

[0015] Furthermore, in step (1), the acid anhydride is acetic anhydride.

[0016] Furthermore, in step (1), the base is one or more of triethylamine and piperidine.

[0017] Further, in step (1), compound 4 is etherified with 2-methoxypropylene to prepare compound 3', and the molar ratio of compound 4 to 2-methoxypropylene ether is 1:1 to 1.3.

[0018] Further, in step (2), the molar ratio of compound 3 to compound 2 is 1:1 to 1.5, and deprotection is performed under weak base and low temperature conditions. The molar ratio of compound 3 to base is 1:1 to 1.1, and the weak base is one of alkali metal carbonate or bicarbonate. The deprotection temperature is 0 to 10°C.

[0019] Further, in step (2), the molar ratio of compound 3' to compound 2 is 1:1 to 1.5, and the protection is removed under acidic conditions, wherein the acid is any one of hydrochloric acid, sulfuric acid, and acetic acid.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] (1) The preparation method of the present invention avoids the use of silicon-based protective groups and avoids the generation of silicon-containing waste liquid, which is more environmentally friendly.

[0022] (2) The preparation method of the present invention uses acid anhydride or 2-methoxypropylene, which has a lower material cost compared with silicon-based protective reagents, thus greatly reducing the material cost.

[0023] (3) The preparation method of the present invention adopts deesterification protection under weak base and low temperature conditions. By controlling the equivalence and conditions of the base, the property of tert-butyl ester being more stable under alkaline conditions is utilized to avoid the removal of terminal tert-butyl ester.

[0024] (4) The method of the present invention effectively solves the problems of cumbersome steps and high cost in the existing synthetic routes. At the same time, the reaction conditions of the entire synthetic route are mild, the operation is convenient, the yield is high, and it is suitable for large-scale industrial production. Attached Figure Description

[0025] Figure 1 The results are from Example 1.

[0026] Figure 2 The results are from Example 2. Detailed Implementation

[0027] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0028] Example 1: Synthesis of Compound 3

[0029]

[0030] Compound 4 (12 g, 100 mmol), triethylamine (11.1 g, 110 mmol), and dichloromethane (50 ml) were added to the reaction flask and stirred until dissolved. Acetic anhydride (11.2 g, 110 mmol) was then added dropwise to the system, and the reaction was carried out at room temperature for 4 h.

[0031] After the reaction was complete, the system was washed twice with water, the organic layer was separated and the dry solvent was recovered under reduced pressure to give compound 3 (15.56 g, 96.3 mmol), with a yield of 96.3%.

[0032] like Figure 1 As shown, the three points from left to right represent the reaction system, the mixing point, and the compound 3 reference standard, respectively. The conditions are ethyl acetate:n-hexane = 1:2, potassium permanganate staining, and the control shows that the reaction successfully synthesized compound 3.

[0033] Example 2 Synthesis of Compound 1

[0034]

[0035] Add tetrahydrofuran (50 ml) and zinc powder (9.8 g, 150 mmol) to the reaction flask; heat to 65-75 °C and reflux. During reflux, add 50 ml of tetrahydrofuran solution of compound 3 (16.16 g, 100 mmol) dropwise over 0.5 h. After the addition is complete, maintain the reflux temperature and stir for 15 min. Then, while maintaining the reflux temperature, continue to add compound 2 (25.36 g, 130 mmol) dropwise over 1-2 h. After the addition is complete, take a sample and spot it onto a TLC plate to confirm the reaction is complete.

[0036] Tetrahydrofuran was recovered under reduced pressure, methyl tert-butyl ether (100 ml) was added, the temperature was lowered to 0–10 °C, and 1 mol / L sodium carbonate solution (10.6 g, 100 mmol, 100 ml) was added. The mixture was stirred for 20 min, allowed to stand and separate into layers, and the aqueous phase was extracted twice with methyl tert-butyl ether. The organic phases were combined and desoluble to dryness to give compound 1 (20.45 g, 86.4 mmol), with a yield of 86.4%.

[0037] like Figure 2 As shown, the three points from left to right represent compound 3, the reaction system, and compound 1 (reference standard). The conditions are ethyl acetate:n-hexane = 1:2. Potassium permanganate staining is used to confirm that the reaction successfully synthesized compound 1.

[0038] Example 3 Synthesis of compound 3'

[0039]

[0040] Add compound 4 (12 g, 100 mmol) and tetrahydrofuran (60 ml) to the reaction flask, cool to 0–10 °C, add 2-methoxypropene (7.9 g, 110 mmol) dropwise, and maintain the temperature for reaction.

[0041] After the reaction was complete, saturated sodium bicarbonate was added and stirred for 10 min. The aqueous layer was extracted once with dichloromethane. The dichloromethane layers were combined, washed once with water, and evaporated to dryness to give compound 3' (15.29 g, 95.8 mmol), with a yield of 95.8%.

[0042] Example 4 Synthesis of Compound 1

[0043]

[0044] Add tetrahydrofuran (50 ml) and zinc powder (9.8 g, 150 mmol) to the reaction flask; heat to 65-75 °C and reflux. During reflux, add a tetrahydrofuran solution (50 ml) of compound 3' (15.96 g, 100 mmol) dropwise over 0.5 h. After the addition is complete, maintain the reflux temperature and stir for 15 min. Then, while maintaining the reflux temperature, continue to add compound 2 (25.36 g, 130 mmol) dropwise over 1-2 h. After the addition is complete, take a sample and spot it onto a TLC plate to confirm the reaction is complete.

[0045] Tetrahydrofuran was recovered under reduced pressure, methyl tert-butyl ether (100 ml) was added, and quenching was performed with 2N hydrochloric acid (3.65 g, 100 mmol, 50 ml). The mixture was allowed to stand and separate into layers. The aqueous phase was extracted twice more with methyl tert-butyl ether. The organic phases were combined and desoluble to dryness to give compound 1 (20.07 g, 84.8 mmol), with a yield of 84.8%.

[0046] Examples 5-6

[0047] Other conditions are the same as in Example 1, except that the molar ratio of compound 4, acid anhydride, and base is changed. The reaction conditions and yields of Examples 1 and 5-6 are detailed in Table 1.

[0048] Table 1. Results under different conditions in Examples 1 and 5-6

[0049] 1 1:1.1:1.1 96.3 5 1:1:1 92.6 6 1:1.2:1.2 94.3

[0050] Examples 7-11

[0051] Other conditions are the same as in Example 2, except that the molar ratio of compound 3 to compound 2, the molar ratio of compound 3 to the base, the type of weak base, and the deprotection temperature are changed. The reaction conditions and yields of Examples 2 and 7-11 are detailed in Table 2.

[0052] Table 2. Results under different conditions in Examples 2 and 7-11

[0053] 2 1:1.3 1:1 Sodium carbonate 0～10℃ 86.4 7 1:1 1:1 Sodium carbonate 0～10℃ 82.3 8 1:1.5 1:1 Sodium carbonate 0～10℃ 84.4 9 1:1.3 1:1.1 Sodium carbonate 0～10℃ 84.8 10 1:1.3 1:1 Potassium carbonate 0～10℃ 82.6 11 1:1.3 1:1 Sodium carbonate 20～30℃ 77.7

[0054] Examples 12-13

[0055] Other conditions are the same as in Example 3, except that the molar ratio of compound 4 to 2-methoxypropylene is changed. The reaction conditions and yields of Examples 3 and 12-13 are detailed in Table 3.

[0056] Table 3. Results under different conditions in Examples 3 and 12-13

[0057] 3 1:1.1 95.8 12 1:1 92.1 13 1:1.3 93.5

[0058] Examples 14-16

[0059] Other conditions are the same as in Example 4, except that the molar ratio of compound 3' to compound 2 and the type of acid are changed. The reaction conditions and yields of Examples 4 and 14-16 are detailed in Table 4.

[0060] Table 4. Results under different conditions in Examples 4 and 14-16

[0061] 4 1:1.3 hydrochloric acid 84.8 14 1:1 hydrochloric acid 81.6 15 1:1.5 hydrochloric acid 83.3 16 1:1.3 sulfuric acid 81.4

[0062] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a rosuvastatin calcium intermediate, characterized in that, The rosuvastatin calcium intermediate is... Its synthetic route is as follows: ； Wherein, R represents a C1~C3 alkyl group, and X and Y represent halogens; a base is used as an acid-binding agent, and the molar ratio of compound 4, acid anhydride, and base is 1:1~1.2:1~1.

2.

2. The method for preparing the rosuvastatin calcium intermediate according to claim 1, characterized in that: The acid anhydride is acetic anhydride.

3. The method for preparing the rosuvastatin calcium intermediate according to claim 1, characterized in that: The base is one or more of triethylamine and piperidine.

4. The method for preparing the rosuvastatin calcium intermediate according to claim 1, characterized in that: The molar ratio of compound 3 to compound 2 is 1:1 to 1.

5. Deprotection is performed under weak base and low temperature conditions. The molar ratio of compound 3 to base is 1:1 to 1.

1. The weak base is one of alkali metal carbonate or bicarbonate. The deprotection temperature is 0 to 10°C.

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