Preparation method of 3-oxo-1-oxa-8-azaspiro [4.5] decane-8-tert-butyl formate

Abstract

The invention relates to the field of synthesis of drug intermediates, in particular to a preparation method of 3-oxo-1-oxa-8-azaspiro [4.5] decane-8-tert-butyl formate. The preparation method comprises the following steps: carrying out condensation reaction on a compound III (4-ethoxycarbonyl methylene-1-tert-butyl piperidinecarboxylate) and methyl glycolate to generate a five-membered ring, and preparing to obtain a compound IV; according to the preparation method, tert-butyl 3-oxo-1-oxa-8-azaspiro [4.5] decane-8-formate (compound I) is prepared through a decarboxylation reaction of the compound IV, and the total yield of the reaction can reach 88.73%. The preparation method provided by the invention has the advantages of easily available raw materials, simple operation and high reaction yield.

Description

A method for preparing tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a method for preparing tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. Background Technology

[0002] tert-butyl oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (CAS: 954236-44-3) is an important pharmaceutical intermediate. US20110230493A1 reports the following synthetic method:

[0003] Where R 1 R 2 R 4 When both are H, compound C1 is N-Boc-4-piperidinone and compound C4 is tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate.

[0004] Specific reagents and conditions: (1) Step 1: 3-bromo-1-propene, tetrahydrofuran, saturated ammonium chloride solution and zinc; reacted overnight at 10°C with stirring. After the reaction was completed, the mixture was acidified with 10% H2SO4, extracted with methyl tert-butyl ether, washed with saturated sodium bicarbonate solution and brine, and then evaporated to dryness to obtain compound C2 with a yield of 95%; (2) Step 2: sodium periodate, Na2S2O5, 2-methyl-2-propanol and water; reacted at 50°C for 7 hours, and then at room temperature for 48 hours. After the reaction was completed, the reaction solution was separated into layers. The organic phase was washed with saturated Na2S2O3 and brine and then evaporated to dryness to obtain crude product C3 with a yield of 80%. The crude product C3 was further purified based on Flash chromatography, and the purification yield was 35%; (3) Step 3: pyridine trioxide, dimethyl sulfoxide, triethylamine; reacted at room temperature for 2 hours. h. After the reaction was completed, the reaction solution was poured into an ice-water bath, extracted with ethyl acetate, washed with hydrochloric acid, sodium sulfite and brine, dried, filtered and evaporated to dryness, and further purified by Flash chromatography to obtain compound C4 with a yield of 97%.

[0005] The preparation route has the following problems: (1) The reaction takes a long time. Step 1 requires overnight reaction and Step 2 takes up to 55 hours. (2) The reaction reagents are complex. Step 2 uses sodium periodate, a strong oxidant, which easily produces iodine-containing inorganic byproducts that are difficult to handle. Step 3 uses the Paric-Delling oxidation reaction system. The sulfur trioxide pyridine complex has strong hygroscopicity and corrosiveness, so the operation needs to be strictly controlled and the safety is poor. (3) The post-processing of the reaction solution is complicated. The products obtained in Step 2 and Step 3 both need to be purified by chromatography. (4) The yield is low. In particular, the yield of C3 product in Step 2 is only 35% after chromatographic purification. The total yield of the three steps is only 25.8%, which is not suitable for industrial production. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. This method uses inexpensive and readily available raw materials, is easy to operate, has a high yield, and is suitable for industrial production.

[0007] This invention provides a method for preparing tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (compound I), comprising: .

[0008] This invention provides a method for preparing compound I, comprising: .

[0009] In the step of preparing compound IV from compound III, the strong base is sodium hydride; the molar ratio of compound III, methyl glycolate and the strong base is 1:1 to 1.5:1 to 2, and the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

[0010] In the step of preparing compound I from compound IV, the heating temperature is 100-110°C, and the reaction solvent is dimethyl sulfoxide or N,N-dimethylformamide.

[0011] In the step of preparing compound III from compound II, the base is sodium hydroxide or potassium hydroxide, and the reaction solvent is N-methylpyrrolidone; the molar ratio of compound II, triethyl phosphoroacetate and base is 1:1~1.5:1~1.5.

[0012] In some embodiments, in the step of preparing compound III from compound II, the base is sodium hydroxide and the reaction solvent is N-methylpyrrolidone.

[0013] In some embodiments, in the step of preparing compound III from compound II, the raw materials are added dropwise and pre-reacted under nitrogen protection at 0-5°C, and the reaction is completed by heating to 20-25°C.

[0014] Beneficial effects:

[0015] This invention proposes a novel method for preparing tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (compound I). Based on the condensation reaction of compound III (4-ethoxycarbonylmethylene-1-piperidinecarboxylate tert-butyl ester) with methyl glycolate to form a five-membered ring, compound IV is prepared. Compound IV undergoes a decarboxylation reaction to prepare tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (compound I), with an overall yield of 88.73%. Furthermore, using N-Boc-4-piperidinone (compound II) as a starting material, compound III is prepared by a Horner-Wadsworth-Emmons reaction with triethyl phosphoroacetate under alkaline conditions. Compound III is then prepared into compound I via the same route. The preparation of compound I from compound II to compound I involves a total of three steps, with an overall yield of 76.95%. The preparation method proposed in this invention uses readily available raw materials, is simple to operate, and has a high reaction yield. It can realize the rapid laboratory preparation and industrial-scale production of the pharmaceutical intermediate tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. Attached Figure Description

[0016] Figure 1 shows the liquid chromatography detection spectrum of compound I. Detailed Implementation

[0017] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0018] The abbreviations for the reaction reagents mentioned in the instructions are as follows: EA: ethyl acetate; PE: petroleum ether; DMSO: dimethyl sulfoxide.

[0019] Example 1: Preparation of Compound I from Compound III:

[0020] Preparation of Compound IV: Sodium hydride (60%, 64 g, 1.6 mol, 1.2 eq) was added in portions to 1 L of anhydrous tetrahydrofuran. Under nitrogen protection, methyl glycolate (135.1 g, 1.5 mol, 1.0 eq) was added dropwise to the reaction solution using a constant pressure dropping funnel at 0-2 °C, controlling the dropping rate to keep the internal temperature of the reaction solution below 5 °C. After the addition was complete, the temperature was raised to room temperature, and the reaction was stirred for 1 h. Compound III (403.9 g, 1.5 mol, 1.0 eq) was dissolved in 1 L of tetrahydrofuran and added dropwise to the reaction solution, and the reaction was stirred for another 16 h. 1 L of saturated ammonium chloride aqueous solution was added dropwise to the reaction solution, and the mixture was stirred for 10 min. The reaction solution was then rotary evaporated, and the crude product was extracted once with 2 L of ethyl acetate. The organic phase was washed once with 500 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then rotary evaporated to dryness to obtain compound IV, a pale yellow liquid. g, yield 91.65%.

[0021] Preparation of Compound I: Compound IV (392.9 g, 1.2 mol, 1.0 eq) was dissolved in 1.5 L DMSO and reacted at 100-110 °C with stirring for 5 h. TLC showed complete reaction of the starting material. Heating was stopped, and the reaction solution was allowed to cool to room temperature. The reaction solution was transferred to a 10 L reactor, and 3 L water and 2 L methyl tert-butyl ether were added. After stirring for 10 min, the mixture was allowed to stand and separate into layers. After separation, the aqueous phase was returned to the reactor, and 1 L methyl tert-butyl ether was added. After stirring for 10 min, the mixture was allowed to stand and separate into layers. The organic phases were separated again, combined, dried over anhydrous sodium sulfate, and then evaporated to dryness by rotary evaporation to obtain 410 g of crude compound I. The crude compound I was poured into 1 L ethyl acetate and heated to reflux in an oil bath with stirring for 0.5 h. Heating was stopped, and the reaction solution was allowed to cool slowly to room temperature. A white solid precipitated out. After filtration, compound I was obtained as 299.6 g of white solid. g, yield 96.81%, LC purity 99.18%, the liquid chromatography detection spectrum of compound I is shown in Figure 1.

[0022] Example 2: Preparation of Compound I from Compound II:

[0023] Preparation of Compound III: Sodium hydroxide (88 g, 2.2 mol, 1.1 eq) was added in portions to 500 mL of N-methylpyrrolidone. The mixture was stirred for 10 min. Under nitrogen protection and at an internal temperature of 0-5 °C, a solution of N-methylpyrrolidone containing 493.2 g, 2.2 mol, 1.1 eq (triethyl phosphoroacetate dissolved in 1 L of N-methylpyrrolidone) was added dropwise. The dropping rate was controlled, and the reaction was maintained at 0-5 °C for approximately 2 h. The addition was completed, and the reaction was continued with stirring at 0-5 °C for another 1 h. Then, a solution of N-methylpyrrolidone containing 398.6 g, 2.0 mol, 1.0 eq (N-Boc-4-piperidinone, 398.6 g, 2.0 mol, 1.0 eq) was added dropwise. The dropping rate was controlled, and the reaction was maintained at 0-5 °C for approximately 3 h. After the initial addition of H was complete, the temperature was slowly raised to 20°C, and the reaction was stirred for 4 h. TLC (PE:EA = 3:1) showed that the starting material had reacted completely. 500 mL of saturated ammonium chloride solution was added dropwise to the reaction solution, and the reaction solution was transferred to a separatory funnel. 2 L of ethyl acetate was added for extraction. The organic phase was washed twice with 500 mL of water each time. After cooling for 20 h, a white solid precipitated. The solid was filtered to obtain 467.1 g of compound III, with a yield of 86.73% and a GC purity of 99.3%.

[0024] Preparation of Compound IV: Sodium hydride (60%, 90 g, 2.25 mol, 1.5 eq) was added in portions to 1 L of anhydrous 2-methyltetrahydrofuran. Under nitrogen protection, methyl glycolate (162.2 g, 1.8 mol, 1.2 eq) was added dropwise using a constant-pressure dropping funnel at 0-2 °C, controlling the dropping rate to ensure the temperature of the reaction solution did not exceed 5 °C. After the addition was complete, the temperature was raised to room temperature, and the reaction was stirred for 1 h. Compound III (403.9 g, 1.5 mol, 1.0 eq) was dissolved in 2 L of anhydrous 2-methyltetrahydrofuran and added dropwise to the reaction solution, and the reaction was stirred for another 16 h. 1 L of saturated ammonium chloride aqueous solution was added dropwise to the reaction solution, and the mixture was stirred for 10 min. The reaction solution was then rotary evaporated, and the crude product was extracted with 2 L of ethyl acetate. The organic phase was washed once with 500 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then rotary evaporated to dryness to obtain compound IV, a pale yellow liquid. 445.60 g, yield 90.73%.

[0025] Preparation of Compound I: Compound IV (392.9 g, 1.2 mol, 1.0 eq) was dissolved in 1.5 L of N,N-dimethylformamide and stirred at 100-110 °C for 5 h. TLC showed that the starting material reacted completely, and heating was stopped. The reaction solution was allowed to cool to room temperature and then transferred to a 10 L reactor. 3 L of water and 2 L of methyl tert-butyl ether were added, and the mixture was stirred for 10 min and allowed to stand for separation. After separation, the aqueous phase was poured back into the reactor, 1 L of methyl tert-butyl ether was added, and the mixture was stirred for 10 min and allowed to stand for separation. The mixture was separated again, and the organic phases were combined, dried with anhydrous sodium sulfate, and then evaporated to dryness by rotary evaporation to obtain 400 g of crude Compound I. The crude Compound I was poured into 1 L of ethyl acetate and heated to reflux in an oil bath. The mixture was stirred and refluxed for 0.5 h. Heating was stopped, and the reaction solution was allowed to cool slowly to room temperature. A white solid precipitated out. After filtration, 295 g of compound I as a white solid was obtained, with a yield of 95.32% and an LC purity of 98%.

[0026] Example 3: Preparation of Compound III

[0027] Potassium hydroxide (134.6 g, 2.4 mol, 1.2 eq) was added in portions to 500 mL of N-methylpyrrolidone. The mixture was stirred for 10 min. Under nitrogen protection, at 0-5 °C, 1 L of a N-methylpyrrolidone solution of triethyl phosphoroacetate (672.55 g, 3 mol, 1.5 eq) was added dropwise (triethyl phosphoroacetate dissolved in 1 L of N-methylpyrrolidone). The addition rate was controlled, and the reaction was maintained at 0-5 °C for approximately 2 h. The addition was completed, and the reaction was continued with stirring at 0-5 °C for another 1 h. Then, 1 L of an N-methylpyrrolidone solution of N-Boc-4-piperidinone (compound II, 398.6 g, 2.0 mol, 1 eq) was added dropwise (N-Boc-4-piperidinone dissolved in 1 L of N-methylpyrrolidone). The addition rate was controlled, and the reaction was maintained at 0-5 °C for approximately 3 h. After the initial addition of H was complete, the temperature was slowly raised to 20°C, and the reaction was stirred for 4 h. TLC (PE:EA = 3:1) showed that the starting material had reacted completely. 500 mL of saturated ammonium chloride solution was added dropwise to the reaction solution, and the reaction solution was transferred to a separatory funnel. 2 L of ethyl acetate was added for extraction. The organic phase was washed twice with 500 mL of water each time. After cooling for 20 h, a white solid precipitated. The solid was filtered to obtain 450.2 g of compound III, with a yield of 83.59% and a GC purity of 98.8%.

Claims

1. A method for preparing compound I, characterized in that, include: 。 2. The method for preparing compound I according to claim 1, characterized in that, include: 。 3. The method for preparing compound I according to claim 1 or 2, characterized in that, In the step of preparing compound IV from compound III, the strong base is sodium hydride.

4. The method for preparing compound I according to claim 1 or 2, characterized in that, In the step of preparing compound IV from compound III, the molar ratio of compound III, methyl glycolate, and strong base is 1:1 to 1.5:1 to 2, and the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran.

5. The method for preparing compound I according to claim 1 or 2, characterized in that, In the step of preparing compound I from compound IV, the heating temperature is 100-110°C.

6. The method for preparing compound I according to claim 1 or 2, characterized in that, In the step of preparing compound I from compound IV, the reaction solvent is dimethyl sulfoxide or N,N-dimethylformamide.

7. The method for preparing compound I according to claim 2, characterized in that, In the step of preparing compound III from compound II, the base is sodium hydroxide or potassium hydroxide, and the reaction solvent is N-methylpyrrolidone.

8. The method for preparing compound I according to claim 2, characterized in that, In the step of preparing compound III from compound II, the molar ratio of compound II, triethyl phosphoroacetate and base is 1:1~1.5:1~1.

5.

9. The method for preparing compound I according to claim 2, characterized in that, In the step of preparing compound III from compound II, the base is sodium hydroxide and the reaction solvent is N-methylpyrrolidone.

10. The method for preparing compound I according to claim 2, characterized in that, In the step of preparing compound III from compound II, the raw materials are added dropwise and pre-reacted under nitrogen protection at 0~5℃, and the reaction is completed by raising the temperature to 20~25℃.

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