A key intermediate of 3-hydroxymethylazine-1-carboxylic acid tert-butyl ester and its preparation method

Abstract

This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a key intermediate of 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester and its preparation method. The method includes the following steps: Ylide reagent is prepared based on the reaction of benzylchloromethyl ether and triphenylphosphine. Without post-treatment, it is directly reacted with compound II (1-diphenylmethylaziridine-3-one) under alkaline conditions to prepare the key intermediate compound III; compound III undergoes catalytic hydrogenation to prepare compound IV; compound IV reacts with di-tert-butyl dicarbonate to prepare 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester (compound I), with a purity of up to 98.87% and an overall reaction yield of up to 72.36%. The preparation method proposed in this invention uses inexpensive and readily available raw materials, is simple to operate, has a high reaction yield, and is highly safe, making it suitable for the industrial production of the pharmaceutical intermediate 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a key intermediate of 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester and its preparation method. Background Technology

[0002] 3-Hydroxymethylaziridine-1-carboxylic acid tert-butyl ester (CAS: 142253-56-3) is an important pharmaceutical intermediate. The current methods for preparing 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester are as follows: Method 1 (WO2010060952A1): Using 1-N-Boc-3-acetidine carboxylic acid as a raw material, the active borohydride intermediate generated by the reaction of iodine with sodium borohydride is used to reduce the carboxylic acid to hydroxymethyl to prepare tert-butyl 3-hydroxymethylazhecyclobutane-1-carboxylic acid. The specific preparation method is as follows:

[0003] There are two problems with this preparation method: (1) The preparation of 1-N-Boc-3-acetidine carboxylic acid is relatively complicated. WO2010131145A1 uses 1-(tert-butoxycarbonyl)-3-(methanesulfonyloxy)azabutane as raw material, reacts with sodium cyanide, and then prepares 1-N-Boc-3-acetidine carboxylic acid by alkaline hydrolysis. Sodium cyanide is a highly toxic cyanide, which poses a safety risk. Moreover, the cost of waste treatment is high. At the same time, its reactivity is high, the reaction conditions are not easy to control, and it is easy to cause side reactions. (2) The process of reacting iodine with sodium borohydride to generate an active borohydride intermediate requires strict temperature control. The operation steps are complicated, and the safety requirements for experimental operation are relatively high.

[0004] Method 2 (CN103709085A): Using 1-Boc-3-azacyclobutanone as a starting material, it is first reacted with triphenylmethylphosphorus bromide (MTPBB) to form a double bond, followed by a borohydride oxidation reaction to prepare 3-hydroxymethylazacyclobutane-1-carboxylic acid tert-butyl ester. The specific reaction equation is as follows:

[0005] However, this preparation method requires the use of boranetetrahydrofuran complex, which has a relatively low concentration, resulting in low reaction efficiency. Furthermore, the reaction temperature must be strictly controlled to prevent leakage, making the process quite dangerous. In addition, the borohydride oxidation reaction also requires the use of hydrogen peroxide solution, which limits this preparation method to small-scale synthesis and makes it unsuitable 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 key intermediate of 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester and its preparation method. The method uses inexpensive and readily available raw materials, is simple to operate, has a high yield, and is highly safe, making it suitable for industrial-scale production.

[0007] This invention provides a compound with structural formula (III): .

[0008] The present invention also provides a method for preparing compound III, comprising: , First, benzyl chloromethyl ether and triphenylphosphine are added, and the reaction is carried out at 70-90°C under nitrogen protection; under alkaline conditions, a solution of compound II is added, and the reaction is carried out at 45-50°C to obtain compound III.

[0009] The base is one of potassium tert-butoxide, sodium tert-butoxide, or sodium hydride, and the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran; the molar ratio of compound II, triphenylphosphine, benzylchloromethyl ether, and the base is 1:1~1.5:1~1.5:1~2.

[0010] After the reaction is complete, a quencher is added to the reaction solution, and compound III is obtained by vacuum distillation, extraction, concentration, and recrystallization. In some embodiments, the quencher is a saturated ammonium chloride solution, the solvent used for extraction is methyl tert-butyl ether, and the solvent used for recrystallization is ethyl acetate.

[0011] This invention provides a method for preparing compound I, comprising: , To prepare compound III from compound II, benzylchloromethyl ether and triphenylphosphine are first added, and the reaction is carried out at 70-90°C under nitrogen protection; under alkaline conditions, a solution of compound II is added, and the reaction is carried out at 45-50°C to obtain compound III.

[0012] In the step of preparing compound IV from compound III, the catalyst is palladium on carbon, and the reaction solvent is one of ethanol, methanol, or isopropanol.

[0013] In the step of preparing compound I from compound IV, the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, and the molar ratio of compound IV, ditert-butyl dicarbonate, and base is 1:1 to 1.5:1 to 2.

[0014] In the step of preparing compound I from compound IV, after the reaction is completed, the reaction solution is extracted, dried, concentrated under reduced pressure, and recrystallized to obtain compound I; in some embodiments, the solvent used for extraction is ethyl acetate, and the solvent used for recrystallization is n-heptane.

[0015] Beneficial effects: This invention proposes a novel key intermediate for 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester (compound I) and its preparation method. This method is based on the reaction of benzylchloromethyl ether and triphenylphosphine to obtain the Ylide reagent. Without post-treatment, it directly reacts with compound II (1-diphenylmethylaziridine-3-one) under alkaline conditions to generate a benzyl-protected alkenyl ether (key intermediate compound III). This intermediate compound is a novel compound. The yield of this step can reach 75.36%, and the purity can reach 98.5%. Further, compound III undergoes a catalytic hydrogenation reaction to prepare aziridine-3-ylmethanol (compound IV), with a yield of 99.48%. Compound IV reacts with di-tert-butyl dicarbonate, and after simple post-treatment, 3-hydroxymethylaziridine-1-carboxylic acid tert-butyl ester (compound I) can be prepared. The yield of this step can reach 96.52%, and the purity can reach 98.87%. The overall yield of the three steps is 72.36%. The preparation method proposed in this invention uses inexpensive and readily available raw materials, is simple to operate, has a high reaction yield, does not use hazardous reagents during the entire reaction process, and generates a small amount of waste. It can realize the industrial-scale production of the pharmaceutical intermediate 3-hydroxymethylazacyclobutane-1-carboxylic acid tert-butyl ester, and has high economic value. Attached Figure Description

[0016] Figure 1 This is the liquid chromatography detection spectrum of compound I; Figure 2 This is the NMR 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: NaBH4: Sodium borohydride; THF: Tetrahydrofuran; MTPBB: Triphenylmethylphosphine bromide; H2O2: Hydrogen peroxide; BH3·THF: Boranetetrahydrofuran complex; PPh3: Triphenylphosphine; BnOCH2Cl: Benzylchloromethyl ether; Pd / C: Palladium on carbon; (Boc)2O: Ditert-butyl dicarbonate.

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

[0020] Add 20 L of tetrahydrofuran to a 50 L jacketed reactor, start mechanical stirring, and add triphenylphosphine (1442.7 g, 5.5 mol, 1.1 eq) and benzylchloromethyl ether (861.3 g, 5.5 mol, 1.1 eq) in batches. After the addition is complete, the reaction system is purged with nitrogen three times and protected with nitrogen. Heat is then introduced through heat transfer oil to maintain an internal temperature of 80 °C for 6 h. The reactor is then cooled to an internal temperature of 20-25 °C, and potassium tert-butoxide (673.2 g, 6 mol, 1.2 eq) is added in batches using a solid feeder. The addition of potassium tert-butoxide is exothermic and should be done slowly, taking about 1 h to complete. After the addition of potassium tert-butoxide, the internal temperature is maintained at 45-50 °C for 2 h, and the reaction solution turns dark brown. 1-Diphenylmethylazacyclobutane-3-one (compound II, 1186.5 g, 5 mol, 1 eq) is added dropwise to the reactor. A tetrahydrofuran solution (1186.5 g of 1-diphenylmethylazine-3-one dissolved in 5 L of tetrahydrofuran) was prepared. The dropping rate was controlled so that the internal temperature did not exceed 55 °C. The dropping was completed in about 2 hours. After the dropping was completed, the internal temperature was maintained at 45~50 °C for 1 hour.

[0021] TLC showed that the reaction of starting material compound II was complete. The mixture was cooled to an internal temperature of 5-10°C, and 10 L of saturated ammonium chloride solution was added dropwise. After the addition was complete, a water pump was connected for vacuum distillation to remove most of the tetrahydrofuran. 10 L of methyl tert-butyl ether was added to the reaction vessel, stirred for 10 min, allowed to stand, and separated. The aqueous phase was returned to the reaction vessel, and another 10 L of methyl tert-butyl ether was added. The mixture was stirred for 10 min, allowed to stand, and separated. The organic phases were combined. The organic phase was rotary evaporated to obtain 2163 g of crude compound III, a pale yellow viscous liquid. 6 L of ethyl acetate was added, and the mixture was heated to reflux for 1 h. Heating was stopped, and the reaction solution was allowed to cool slowly to room temperature. A white solid precipitated. The solid was filtered, and the filter cake was washed once with 500 mL of ethyl acetate to obtain 1286.8 g of pure compound III, with a yield of 75.36% and a liquid phase purity of 98.5%. LC-MS (ESI) calcd for C 24 H 23 NO [M+H] + m / z 342.45, found 342.25.

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

[0023] Preparation of Compound III

[0024] Add 20 L of 2-methyltetrahydrofuran to a 50 L jacketed reactor, start mechanical stirring, and add triphenylphosphine (1967.25 g, 7.5 mol, 1.5 eq) and benzylchloromethyl ether (1174.5 g, 7.5 mol, 1.5 eq) in batches. After the addition is complete, purge the reaction system with nitrogen three times and protect it with nitrogen. Heat the system with heat transfer oil to maintain an internal temperature of 90 °C and react for 5 h. Cool the reactor to 20-25 °C, and add sodium hydride (60%, 360 g, 9 mol, 1.8 eq) in batches using a solid feeder. Before adding sodium hydride, the reactor needs to be equipped with a drying tube (to prevent moisture from entering). The addition of sodium hydride is exothermic, so add it slowly. Strictly control the internal temperature at 40-45 °C during the addition phase, and complete the addition in about 1.5-2 h. After the sodium hydride is added, maintain the internal temperature at 45-50 °C for 2 hours. h, the reaction solution turns dark brown; add dropwise a 2-methyltetrahydrofuran solution of 1-diphenylmethylazacyclobutane-3-one (compound II, 1186.5 g, 5 mol, 1 eq) to the reaction vessel (dissolve 1186.5 g of 1-diphenylmethylazacyclobutane-3-one in 5 L of 2-methyltetrahydrofuran), controlling the dropping rate to keep the internal temperature below 55℃, and complete the addition in about 2 h. After the addition is complete, maintain the internal temperature at 45~50℃ for 1 h.

[0025] TLC showed that the reaction of starting material compound II was complete. The mixture was cooled to an internal temperature of 5-10°C, and 10 L of saturated ammonium chloride solution was added dropwise. After the addition was complete, a water pump was connected for vacuum distillation to remove most of the 2-methyltetrahydrofuran. 10 L of methyl tert-butyl ether was added to the reaction vessel, stirred for 10 min, allowed to stand, and separated. The aqueous phase was returned to the reaction vessel, and another 10 L of methyl tert-butyl ether was added. The mixture was stirred for 10 min, allowed to stand, and separated. The organic phases were combined and rotary evaporated to obtain 2161 g of crude compound III, a pale yellow viscous liquid. 6 L of ethyl acetate was added, and the mixture was heated to reflux for 1 h. Heating was stopped, and the reaction solution was allowed to cool slowly to room temperature, resulting in the precipitation of a white solid. The solid was filtered, and the filter cake was washed once with 500 mL of ethyl acetate to obtain 1280.6 g of pure compound III, with a yield of 75.01% and a liquid phase purity of 98.2%.

[0026] Preparation of compound IV

[0027] Add 3 L of ethanol to a 5 L four-necked flask, and add compound III (1024.5 g, 3 mol, 1 eq) and Pd / C (20 g) while stirring. Purify the reaction system with nitrogen three times, and then with hydrogen three times. Connect the four-necked flask to a 5 L gas bag containing hydrogen. During the reaction, the gas bag will shrink, and hydrogen will be added again. Maintain the reaction at room temperature for 8 h. TLC shows that the starting material has reacted completely. Filter the reaction solution through a sand core funnel containing diatomaceous earth. Dry the filtrate to obtain 260 g of crude compound IV, with a yield of 99.48%. Proceed directly to the next step.

[0028] Preparation of Compound I

[0029] Pour 3 L of water into a four-necked flask, add sodium hydroxide (132 g, 3.3 mol, 1.1 eq) while stirring, stir for 10 min, add an aqueous solution of crude compound IV (260 g, 3 mol, 1 eq) (dissolve 260 g of crude compound IV in 1 L of water), heat the reaction solution in an oil bath, transfer di-tert-butyl dicarbonate (720.4 g, 3.3 mol, 1.1 eq) to a constant pressure dropping funnel, and add di-tert-butyl dicarbonate dropwise to the reaction solution when the internal temperature is 25-30℃. The addition is exothermic and gas release is obvious. Control the dropping rate to keep the internal temperature below 35℃. The addition is completed in about 2 h, and the reaction is continued at an internal temperature of 25-30℃ for 1 h.

[0030] Add 5 L of ethyl acetate to the reaction solution and stir for 10 min. After separation, pour the aqueous phase back into the four-necked flask, add 5 L of ethyl acetate, stir for 10 min, and separate again. Combine the ethyl acetate phases, dry with anhydrous sodium sulfate, and concentrate the ethyl acetate phase under reduced pressure to obtain crude compound I. Dissolve crude compound I in 2 L of n-heptane and heat to 50-55°C until all crude compound I dissolves. Continue stirring for 1 h, then stop heating and allow the reaction solution to cool slowly to room temperature. A white solid precipitates out. Filter the solution, wash the filter cake once with 500 mL of n-heptane to obtain 542.1 g of compound I as a white powder, with a yield of 96.52% and a liquid chromatography purity of 98.87%. The liquid chromatography chromatogram of compound I is shown below. Figure 1 As shown, the nuclear magnetic resonance spectrum is as follows: Figure 2 As shown.

[0031] Example 3: Compound III was used to prepare compound I:

[0032] Preparation of compound IV

[0033] Add 3 L of isopropanol to a 5 L four-necked flask, and add compound III (1024.5 g, 3 mol, 1 eq) and Pd / C (20 g) while stirring. Purify the reaction system with nitrogen three times, and then with hydrogen three times. Connect the four-necked flask to a 5 L gas bag containing hydrogen. During the reaction, the gas bag will shrink, and hydrogen will be added again. Maintain the reaction at room temperature for 8 h. TLC shows that the starting material has reacted completely. Filter the reaction solution through a sand core funnel containing diatomaceous earth. Dry the filtrate to obtain 260 g of crude compound IV, with a yield of 99.48%. Proceed directly to the next step.

[0034] Preparation of Compound I

[0035] Pour 3 L of water into a four-necked flask, add potassium hydroxide (336.7 g, 6 mol, 2 eq) while stirring, stir for 10 min, add an aqueous solution of crude compound IV (260 g, 3 mol, 1 eq) (dissolve 260 g of crude compound IV in 1 L of water), heat the reaction solution in an oil bath, transfer di-tert-butyl dicarbonate (982.35 g, 4.5 mol, 1.5 eq) to a constant pressure dropping funnel, and add di-tert-butyl dicarbonate dropwise to the reaction solution when the internal temperature is 25-30℃. The addition is exothermic and gas release is obvious. Control the dropping rate to keep the internal temperature below 35℃. The addition is completed in about 2 h, and the reaction is continued at an internal temperature of 25-30℃ for 1 h.

[0036] Add 5 L of ethyl acetate to the reaction solution and stir for 10 min. After separation, pour the aqueous phase back into the four-necked flask, add 5 L of ethyl acetate, stir for 10 min, and separate again. Combine the ethyl acetate phases and dry with anhydrous sodium sulfate. Concentrate the ethyl acetate phase under reduced pressure to obtain crude compound I. Dissolve crude compound I in 2 L of n-heptane and heat to 50-55 °C until all crude compound I dissolves. Continue stirring for 1 h, then stop heating and allow the reaction solution to cool slowly to room temperature. A white solid precipitates out. Filter the solution and wash the filter cake once with 500 mL of n-heptane to obtain 541.8 g of compound I as a white powder, with a yield of 96.45% and a liquid phase purity of 98.75%.

Claims

1. Compounds with structural formula (III): 。 2. A method for preparing compound III according to claim 1, characterized in that, include: ， First, benzyl chloromethyl ether and triphenylphosphine are added, and the reaction is carried out at 70-90°C under nitrogen protection; under alkaline conditions, a solution of compound II is added, and the reaction is carried out at 45-50°C to obtain compound III.

3. The method for preparing compound III according to claim 2, characterized in that, The base is one of potassium tert-butoxide, sodium tert-butoxide, or sodium hydride, and the reaction solvent is tetrahydrofuran or 2-methyltetrahydrofuran; the molar ratio of compound II, triphenylphosphine, benzylchloromethyl ether, and the base is 1:1~1.5:1~1.5:1~2.

4. The method for preparing compound III according to claim 2, characterized in that, After the reaction was completed, a quenching agent was added to the reaction solution, and compound III was obtained by vacuum distillation, extraction, concentration and recrystallization.

5. The method for preparing compound III according to claim 4, characterized in that, The quenching agent is a saturated ammonium chloride solution, the solvent used for extraction is methyl tert-butyl ether, and the solvent used for recrystallization is ethyl acetate.

6. A method for preparing compound I, characterized in that, include: ， To prepare compound III from compound II, benzylchloromethyl ether and triphenylphosphine are first added, and the reaction is carried out at 70-90°C under nitrogen protection; under alkaline conditions, a solution of compound II is added, and the reaction is carried out at 45-50°C to obtain compound III.

7. The method for preparing compound I according to claim 6, characterized in that, In the step of preparing compound IV from compound III, the catalyst is palladium on carbon, and the reaction solvent is one of ethanol, methanol, or isopropanol.

8. The method for preparing compound I according to claim 6, characterized in that, In the step of preparing compound I from compound IV, the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, and the molar ratio of compound IV, ditert-butyl dicarbonate, and base is 1:1 to 1.5:1 to 2.

9. The method for preparing compound I according to claim 6, characterized in that, In the step of preparing compound I from compound IV, after the reaction is completed, the reaction solution is extracted, dried, concentrated under reduced pressure, and recrystallized to obtain compound I.

10. The method for preparing compound I according to claim 9, characterized in that, The solvent used for extraction was ethyl acetate, and the solvent used for recrystallization was n-heptane.

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