A synthetic process for (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester
By using CBr4 and triphenylphosphine for the initial reaction, followed by heating the reaction in DMSO with sodium bicarbonate as a catalyst, the problems of high energy consumption and strong equipment corrosion in the existing technology are solved. This achieves the efficient and safe preparation of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU ALPHA PHARM CO LTD
- Filing Date
- 2026-03-26
- Publication Date
- 2026-05-26
AI Technical Summary
Existing technologies for preparing (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester suffer from problems such as high energy consumption, strong equipment corrosion, complex operation, and impact on product quality.
CBr4 was used as the brominating agent and triphenylphosphine as the catalyst. The first step of the reaction was carried out at room temperature, followed by a heating reaction in DMSO with sodium bicarbonate as the catalyst, thus avoiding ultra-low temperature and complex pH adjustment operations.
It achieves mild reaction conditions, reduces energy consumption, minimizes equipment corrosion, simplifies the operation process, and improves reaction yield and product quality, making it suitable for large-scale production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediate synthesis technology, specifically a synthesis process for (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester. Background Technology
[0002] Rosuvastatin was developed by AstraZeneca and was first approved for marketing in the Netherlands in November 2002. It was approved for marketing by the US FDA in August 2003 and approved for marketing in China in 2006. It is now available in many countries and is one of the most widely used statin drugs.
[0003] (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester (compound II) is a key intermediate in the synthesis of statin active pharmaceutical ingredients such as rosuvastatin and pitavastatin. It can be obtained by oxidation of (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester (compound I). The reaction equation is shown below: Currently, the methods reported in the literature for preparing (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester by oxidation of (4R-cis)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester mainly include Swern oxidation, Dess-Martin oxidation, TEMPO / NaBr / NaClO (or TCCA) oxidation, and pyridine sulfur trioxide complex oxidation (Parikh-Doering oxidation).
[0004] US Patent 4970313A and Chinese Patent CN1876644A (Application No. CN200610052219.1) report the Swern oxidation method, which uses oxalyl chloride as an activator. Oxaloyl chloride readily decomposes at room temperature to produce hydrogen chloride gas, which is highly corrosive to equipment. Furthermore, this reaction requires ultra-low temperatures of -78°C, resulting in high energy consumption and the production of malodorous dimethyl sulfide byproducts, causing atmospheric pollution.
[0005] Chinese patent CN102617540A (application number CN201210117031.6) reports a method for preparing (4R-Cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetate tert-butyl ester using a sulfur trioxide pyridine complex as an oxidant. The pyridine sulfur trioxide complex used in this method is expensive and highly corrosive. Furthermore, the pyridine produced during the reaction is difficult to completely remove, affecting product quality.
[0006] US Patent US7161004B2 and European Patent EP2351762B1 report a method for preparing (4R-Cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester using NaClO as an oxidant and TEMPO as a catalyst. The reaction is carried out in a two-phase system of organic solvent and water. If the system is highly alkaline, the tert-butyl ester will hydrolyze, affecting the yield. Therefore, the NaClO solution needs to be pre-adjusted to a specific pH value and slowly added dropwise to the reaction system, which is cumbersome and not conducive to industrial production. Summary of the Invention
[0007] To address the above shortcomings, the present invention provides the following technical solution: A process for synthesizing (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, characterized by comprising the following steps: First, compound I was dissolved in an organic solvent, a brominating agent was added, and then a catalyst was added. The mixture was stirred at room temperature for 3-5 hours. After the reaction was completed, the product was separated to obtain compound II. In the second step, compound II was dissolved in an organic solvent, a catalyst was added, and the mixture was heated to react. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III.
[0008] Furthermore, the organic solvent used in the first step reaction is dichloromethane.
[0009] Furthermore, the catalyst used in the first step reaction is triphenylphosphine.
[0010] Furthermore, the brominating reagent used in the first step reaction is CBr4.
[0011] Furthermore, the amount of catalyst used in the first step reaction is 1 to 2 eq of compound I.
[0012] Furthermore, the amount of brominating reagent used in the first step reaction is 1 to 2 eq of compound I.
[0013] Furthermore, the reaction temperature in the second step is 50–100°C.
[0014] Furthermore, the solvent used in the second step of the reaction is DMSO.
[0015] Furthermore, the catalyst used in the second step reaction is sodium bicarbonate.
[0016] Furthermore, the amount of catalyst used in the second step reaction is 2 to 4 eq of compound II.
[0017] The beneficial effects of this invention are: 1. The process route of this invention has mild reaction conditions, which can effectively reduce energy consumption, eliminate the need for expensive cryogenic equipment, reduce equipment corrosion, and lower requirements for reactor materials; 2. The operating environment is friendly, avoiding highly corrosive reagents and complex pH adjustment operations, significantly improving process safety; 3. The process route of this invention can effectively improve reaction yield, avoid by-product and product loss due to hydrolysis, ensure product quality, and is suitable for the needs of large-scale, continuous production. Attached Figure Description
[0018] Figure 1 This is a schematic diagram of the original oxidation reaction process of the present invention; Figure 2 This is a schematic diagram of the oxidation reaction process of the present invention. Detailed Implementation
[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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. Example 1
[0020] At room temperature, 26.0 g (0.1 mol) of compound 1 was dissolved in CH2Cl2 (250 ml), CBr4 (0.15 mol) was added, followed by triphenylphosphine (0.15 mol). The reaction mixture was stirred for 3–5 hours, the solvent was removed under vacuum, 100 ml of dichloromethane was added to dissolve the compound, and the mixture was washed 2–3 times with saturated brine. The organic phase was separated, and the product was recrystallized from 40 ml of toluene to give 30.9 g of compound II, with a yield of 95.7% and a purity of 99.3%. In the second step, 32.3 g of 0.1 mol of compound II was dissolved in 1.5–2 eq of organic solvent DMSO, and 2 eq of sodium bicarbonate powder as catalyst were added. The mixture was heated to 50–60 °C and reacted for 2–3 h. The reaction was monitored by HPLC. After the reaction was completed, the mixture was neutralized to neutral with dilute hydrochloric acid, the solvent was removed under vacuum, and 200 ml of dichloromethane was added to dissolve the compound. The mixture was washed 2–3 times with saturated brine, the organic phase was separated, and the product was recrystallized from 40 ml of toluene to obtain 24.5 g of compound III, with a yield of 94.9% and a purity of 99.3%. Example 2
[0021] At room temperature, 26.0 g (0.1 mol) of compound 1 was dissolved in CH2Cl2 (250 ml), CBr4 (0.2 mol) was added, followed by triphenylphosphine (0.2 mol). The reaction mixture was stirred for 3–5 hours, the solvent was removed under vacuum, 100 ml of dichloromethane was added to dissolve the compound, and the mixture was washed 2–3 times with saturated brine. The organic phase was separated, and the product was recrystallized from 40 ml of toluene to give 30.6 g of compound II, with a yield of 94.8% and a purity of 97.3%. Example 3
[0022] At room temperature, 26.0 g (0.1 mol) of compound 1 was dissolved in CH2Cl2 (250 ml), CBr4 (0.1 mol) was added, followed by triphenylphosphine (0.1 mol). The reaction mixture was stirred for 3–5 hours, the solvent was removed under vacuum, 100 ml of dichloromethane was added to dissolve the compound, and the mixture was washed 2–3 times with saturated brine. The organic phase was separated, and the product was recrystallized from 40 ml of toluene to give 30.2 g of compound II, with a yield of 98.5% and a purity of 99.3%. Example 4
[0023] In the second step, 32.3 g of 0.1 mol of compound II was dissolved in 1.5–2 eq of organic solvent DMSO, and 4 eq of sodium bicarbonate powder was added as catalyst. The mixture was heated to 50–60 °C and the reaction was monitored by HPLC. After the reaction was completed, the mixture was neutralized to neutral with dilute hydrochloric acid, the solvent was removed under vacuum, and 200 ml of dichloromethane was added to dissolve the compound. The mixture was washed 2–3 times with saturated brine, the organic phase was separated, and the product was recrystallized from 40 ml of toluene to obtain 24.3 g of compound III, with a yield of 94.1% and a purity of 98.9%. Example 5
[0024] In the second step, 32.3 g of 0.1 mol of compound II was dissolved in 1.5–2 eq of organic solvent DMSO, and 2 eq of sodium bicarbonate powder as catalyst was added. The mixture was heated to 90–100 °C and the reaction was monitored by HPLC. After the reaction was completed, the mixture was neutralized to neutral with dilute hydrochloric acid, the solvent was removed under vacuum, and 200 ml of dichloromethane was added to dissolve the compound. The mixture was washed 2–3 times with saturated brine, the organic phase was separated, and the product was recrystallized from 40 ml of toluene to obtain 24.1 g of compound III, with a yield of 93.3% and a purity of 99.0%.
[0025] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.
[0026] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.
Claims
1. A process for synthesizing (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester, characterized in that... Includes the following steps: First, compound I was dissolved in an organic solvent, a brominating agent was added, and then a catalyst was added. The mixture was stirred at room temperature for 3-5 hours. After the reaction was completed, the product was separated to obtain compound II. In the second step, compound II was dissolved in an organic solvent, a catalyst was added, and the reaction was heated. The reaction was monitored by HPLC. After the reaction was completed, the product was separated to obtain compound III.
2. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The organic solvent used in the first step reaction is dichloromethane.
3. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The catalyst used in the first step reaction is triphenylphosphine.
4. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The brominating reagent used in the first step reaction is CBr4.
5. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The amount of catalyst used in the first step reaction is 1 to 2 eq of compound I.
6. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The amount of brominating reagent used in the first step reaction is 1 to 2 eq of compound I.
7. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The reaction temperature for the second step is 50–100°C.
8. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The solvent used in the second step of the reaction is DMSO.
9. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The catalyst used in the second step of the reaction is sodium bicarbonate.
10. The synthesis process of (4R-cis)-6-aldehyde-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester according to claim 1, characterized in that: The amount of catalyst used in the second step reaction is 2 to 4 eq of compound II.