A method for synthesizing 7-dibenzylamino-3,5-dioxoheptanoic acid tert-butyl ester

Abstract

The application discloses a synthesis method of 7-dibenzylamino-3,5-dioxoheptanoic acid tert-butyl ester. The method comprises the following steps: taking bromoacetyl acetic acid tert-butyl ester as a starting material, and reacting with compound IV in an organic solvent in the presence of zinc powder and a catalyst; and after the reaction is completed, performing acid post-treatment to obtain 7-dibenzylamino-3,5-dioxoheptanoic acid tert-butyl ester, i.e. compound I. According to the method, dangerous reagents such as sodium hydride and n-butyl lithium are not needed, and only conventional chemical reagents are used, so that the target product can be efficiently prepared under mild reaction conditions.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing tert-butyl 7-dibenzylamino-3,5-dioxonoheptanate. Background Technology

[0002] 7-Dibenzylamino-3,5-dioxoheptanoate (tert-Butyl 7-dibenzylamino-3,5-dioxoheptanoate) is an important organic synthetic intermediate with the molecular formula C2. 25 H 31 NO4, with a molecular weight of 409.53, is listed as compound I in route 1. This compound contains a dibenzyl-protected amino group, two ketone carbonyl groups, and a tert-butyl ester group. This multifunctional structure endows it with abundant reaction sites and highly flexible chemical transformation capabilities.

[0003] In the pharmaceutical field, the core application value of 7-dibenzylamino-3,5-dioxoheptanate tert-butyl ester (Compound I) lies in its important role as a key chiral side chain precursor in the synthesis of statins. Using this compound as a starting material, (4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid tert-butyl ester (Compound II) can be prepared through multiple conversion steps. The latter is a key chiral intermediate in the synthesis of atorvastatin. With the continued acceleration of population aging and the year-on-year increase in the incidence of cardiovascular and cerebrovascular diseases in my country, the clinical demand and market size of statins have maintained a steady growth trend. Against this backdrop, developing an efficient, economical, and environmentally friendly synthetic route for 7-dibenzylamino-3,5-dioxoheptanate tert-butyl ester is of significant practical and strategic value for meeting the continuously expanding market demand and reducing the production cost of atorvastatin.

[0004] Route 1: .

[0005] However, there are few reports on the synthesis methods of tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate (compound I). Patent CN101326154 (US2009069579) discloses a synthetic route that uses tert-butyl acetoacetate as a raw material, which is treated with sodium hydride and n-butyllithium, and then condensed with ethyl 3-(dibenzylamino)propionate to obtain the target product (route 2). However, this route has a yield of only 30%, and the sodium hydride and n-butyllithium used are extremely chemically reactive, posing a risk of spontaneous combustion. The reaction needs to be carried out at an ultra-low temperature of -78°C, which places stringent requirements on equipment, results in significantly high energy consumption, and poses prominent safety hazards, making it difficult to meet the needs of large-scale industrial production.

[0006] Route 2: . Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing tert-butyl 7-dibenzylamino-3,5-dioxonanoate, using tert-butyl 4-bromoacetoacetate as a substrate. This method leverages the stronger coordination ability of the carbonyl group compared to the ester group to promote the formation of a six-membered ring intermediate in the reaction, thus overcoming the limitations of traditional α-haloester substrates. This method eliminates the need for hazardous reagents such as sodium hydroxide and n-butyllithium, and can efficiently and safely obtain the target product using only conventional chemicals under mild conditions, making it suitable for industrial production.

[0008] The technical solution adopted by this invention to solve its technical problem is: A method for synthesizing tert-butyl 7-dibenzylamino-3,5-dioxonanoic acid. Starting with tert-butyl bromoacetoacetate, compound IV was reacted with zinc powder and a catalyst in an organic solvent. After the reaction was complete, acid post-treatment yielded tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate, i.e., compound I. In this invention, the halogenated product reacts with zinc to form an organozinc reagent, which then reacts with a cyano group, followed by acidification to yield a ketone carbonyl group.

[0009] Preferably, the catalyst is selected from one or more of trimethylchlorosilane, cuprous bromide, and elemental iodine.

[0010] As a preferred embodiment, the molar ratio of tert-butyl bromoacetoacetate: zinc powder: catalyst: compound IV is 1:1.2-1.5:0.02-0.05:1.

[0011] Preferably, the reaction is carried out under nitrogen or argon protection.

[0012] Preferably, the organic solvent is tetrahydrofuran.

[0013] Preferably, the reaction temperature is 50~70℃ and the total reaction time is 4~6 hours.

[0014] Preferably, the acidic post-treatment involves cooling the reaction product to 0–5°C and adjusting the pH to 2–3 with hydrochloric acid.

[0015] The beneficial effects of this invention are: 1. It avoids the use of hazardous reagents such as sodium hydroxide and n-butyllithium, which are prone to spontaneous combustion, thus ensuring high safety; 2. The reaction conditions are mild, requiring no ultra-low temperature environment, and have low equipment requirements, making them suitable for industrial production; 3. Compared with existing technologies, the yield has been significantly increased from 30.1% to 92.8%, which significantly reduces production costs and emissions of waste gas, wastewater, and solid waste. 4. The process is simple and easy to operate, making it an economical, safe, efficient and environmentally friendly new synthesis process. Detailed Implementation

[0016] The technical solution of the present invention will be further described in detail below through specific embodiments.

[0017] Unless otherwise specified, all raw materials and equipment used in this invention are commercially available or commonly used in the field. Unless otherwise specified, the methods described in the following examples are conventional methods in the field. Zinc powder (7440-66-6) was purchased from Anaiji Chemical. The preparation of compound III in this invention follows the synthesis method of compound IV in the applicant's prior application (application number 2026108397642).

[0018] Example 1: Preparation of Compound IV Dibenzylamine (1.0 kg, 1.0 eq), water (5.0 L), and acrylonitrile (322.8 g, 1.2 eq) were added to a reaction flask, and the mixture was heated to 60 °C and stirred for 16 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature and extracted twice with ethyl acetate. The organic phases were combined and washed once each with 10% citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oily liquid, which was compound IV (1206.8 g), with a yield of 95.1%. 1 H NMR (300 MHz, CDCl3) δ 7.49 – 7.24 (m, 11H), 3.67 (s, 4H), 2.82 (t,J = 6.9 Hz, 2H), 2.44 (t,J = 6.9 Hz, 2H).

[0019] Example 2: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) Under nitrogen protection, zinc powder (33.1 g, 1.2 eq), tetrahydrofuran (500 mL), and trimethylchlorosilane (2.3 g, 0.05 eq) were added to a reaction flask. After stirring for 0.5 hours, compound IV (105.6 g, 1.0 eq) was added. The mixture was heated to 70 °C, and a tetrahydrofuran solution (100 mL) of compound III (100.0 g, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was kept at 70 °C for 3 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (143.5 g), with a yield of 83.1%. 1 H NMR (300 MHz, CDCl 3, (Predominantly enol structure) δ 7.45-7.16 (m, 10H), 5.46 (s, 1H), 3.58 (s, 4H), 3.19 (s, 2H), 2.78 (t, J = 7.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.44 (s, 9H), the same below.

[0020] Example 3: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) Under nitrogen protection, zinc powder (41.3 g, 1.5 eq), tetrahydrofuran (500 mL), and cuprous bromide (3.0 g, 0.05 eq) were added to the reaction flask. After stirring for 0.5 hours, compound IV (105.6 g, 1.0 eq) was added. The mixture was heated to 70 °C, and a tetrahydrofuran solution (100 mL) of compound III (100.0 g, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was kept at 70 °C for 3 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (149.6 g), with a yield of 86.6%.

[0021] Example 4: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) Under nitrogen protection, zinc powder (41.3 g, 1.5 eq), tetrahydrofuran (500 mL), and iodine (5.4 g, 0.05 eq) were added to the reaction flask. After stirring for 0.5 hours, compound IV (105.6 g, 1.0 eq) was added. The mixture was heated to 70 °C, and a tetrahydrofuran solution (100 mL) of compound III (100.0 g, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was kept at 70 °C for 3 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (148.0 g), with a yield of 85.7%.

[0022] Example 5: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) Under nitrogen protection, zinc powder (33.1 g, 1.2 eq), tetrahydrofuran (500 mL), cuprous bromide (1.2 g, 0.02 eq), and iodine (2.1 g, 0.02 eq) were added to the reaction flask. After stirring for 0.5 hours, compound IV (105.6 g, 1.0 eq) was added. The mixture was heated to 60 °C, and a tetrahydrofuran solution (100 mL) of compound III (100.0 g, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was kept at 60 °C for 5 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (160.3 g), with a yield of 92.8%.

[0023] Example 6: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) Under nitrogen protection, zinc powder (41.3 g, 1.5 eq), tetrahydrofuran (500 mL), cuprous bromide (3.0 g, 0.05 eq), and iodine (5.4 g, 0.05 eq) were added to the reaction flask. After stirring for 0.5 hours, compound IV (105.6 g, 1.0 eq) was added. The mixture was heated to 50 °C, and a tetrahydrofuran solution (100 mL) of compound III (100.0 g, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was kept at 50 °C for 5 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (155.8 g), with a yield of 90.2%.

[0024] Example 7: Preparation of Compound I (tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate) in hundreds of kilograms Under nitrogen protection, zinc powder (33.1 kg, 1.2 eq), tetrahydrofuran (500 L), cuprous bromide (1.2 kg, 0.02 eq), and iodine (2.1 kg, 0.02 eq) were added to the reaction vessel. After stirring for 1 hour, compound IV (105.6 kg, 1.0 eq) was added. The mixture was heated to 60 °C, and a tetrahydrofuran (100 L) solution of compound III (100.0 kg, 1.0 eq) was slowly added dropwise. After the addition was complete, the reaction was maintained at 60 °C for 5 hours. After TLC monitoring showed that the reaction was complete, the reaction solution was cooled to 0–5 °C, and the pH was adjusted to 2–3 with 2 N hydrochloric acid. The mixture was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with n-heptane-ethyl acetate (20:1, volume ratio) at 0–5 °C, the light yellow solid was collected by filtration, and dried under vacuum at 40 °C to constant weight to give compound I (158.2 kg), with a yield of 91.6%.

[0025] Comparative Example 1: Preparation of Compound I Compound I was prepared using Route 2. Under nitrogen protection, sodium hydride (5.1 g, 60% mineral oil, 1.0 eq) and tetrahydrofuran (100 mL) were added to a reaction flask, followed by stirring of compound 7 (20.0 g, 1.0 eq). The reaction mixture was cooled to 0 °C, and n-butyllithium (55.6 mL, 2.5 M, 1.1 eq) was slowly added dropwise, with stirring at 0 °C for 10 minutes. The reaction mixture was then cooled to -78 °C, and compound 6 (37.6 g, 1.0 eq) was added, with stirring continuing for 45 minutes. The reaction mixture was then heated to -30 °C over 30 minutes, held at this temperature for 15 minutes, and then cooled to -78 °C and held for 15 minutes. After the reaction was complete, the reaction mixture was quenched in a pre-cooled mixture of ethyl acetate and pH 10 buffer. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using petroleum ether-ethyl acetate (10:1, volume ratio) as eluent. The target component was collected and concentrated under reduced pressure to obtain a light yellow solid, which was compound I (15.6 g), with a yield of 30.1%.

[0026] To better illustrate the features and advantages of the process of this invention, a comparison is made between the process of this invention and the prior art (Comparative Example 1). The comparison of the key evaluation elements of the two is shown in Table 1 below: Table 1 .

[0027] As shown in Table 1, compared with the prior art, the process of the present invention has mild reaction conditions, significantly improved yield, high operational safety, low reagent cost, and is friendly to industrial scale-up, making it suitable for large-scale industrial production.

[0028] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for synthesizing tert-butyl 7-dibenzylamino-3,5-dioxonanoic acid, characterized in that, Starting with tert-butyl bromoacetoacetate, it reacts with compound IV in an organic solvent in the presence of zinc powder and a catalyst. After the reaction is complete, it is post-treated with acid to obtain tert-butyl 7-dibenzylamino-3,5-dioxoheptanoate, i.e., compound I.

2. The synthesis method according to claim 1, characterized in that, The catalyst is selected from one or more of trimethylchlorosilane, cuprous bromide, and elemental iodine.

3. The synthesis method according to claim 1 or 2, characterized in that, The molar ratio of tert-butyl bromoacetoacetate: zinc powder: catalyst: compound IV is 1:1.2-1.5:0.02-0.05:

1.

4. The synthesis method according to claim 1, characterized in that, The reaction is carried out under nitrogen or argon protection.

5. The synthesis method according to claim 1, characterized in that, The organic solvent is tetrahydrofuran.

6. The synthesis method according to claim 1, characterized in that, The reaction temperature is 50~70℃, and the total reaction time is 4~6 hours.

7. The synthesis method according to claim 1, characterized in that, The acidic post-treatment involves cooling the reaction product to 0–5°C and adjusting the pH to 2–3 with hydrochloric acid.

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