Preparation method of (2R, 4S)-2, 4-bis (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester

Abstract

The invention relates to a preparation method of (2R, 4S)-2, 4-bis (hydroxymethyl) azetidine-1-carboxylic acid tert-butyl ester (a compound as shown in a formula I). The green solvent water is used for replacing methanol or ethanol as a solvent, the reaction safety is improved by using a fixed bed hydrogenation technology, high-selectivity deprotection is realized, and the reaction time is remarkably shortened. And through the modular combination of the continuous reactor, the centrifugal extractor, the wiped-film evaporator and other equipment, the full continuity of the process from reaction to post-treatment is realized. In conclusion, the technical scheme provided by the invention has good economic effects and is suitable for industrial production. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, and particularly to a method for preparing tert-butyl (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate. Background Art

[0002] Tetracyclic azetidine is a very valuable pharmaceutical intermediate, and many marketed drugs or small molecule compounds in the clinical stage contain tetracyclic azetidine fragments. Since the 1980s, PNP (purine nucleoside phosphorylase) has been a biological target selected by many pharmaceutical companies. PNP catalyzes the phosphorolysis of ribonucleosides and deoxyribonucleosides of guanine and hypoxanthine, producing the corresponding sugar-1-phosphate and guanine, hypoxanthine or other purine bases. Since the accumulation of dGTP prevents the stimulation of T lymphocytes, people lacking PNP suffer from specific T cell immunodeficiency. Therefore, PNP inhibitors have immunosuppressive effects and are active against T cell malignancies and T cell proliferative diseases. US 5,985,848, US 6,066,722 and US 6,228,741 describe a class of compounds called Immucillins, which are inhibitors of PNP and purine phosphoribosyltransferase (PPRT). These immunicillins can be used to treat parasitic infections, T cell malignancies, autoimmune diseases and inflammatory diseases. They can also be used for immunosuppression in organ transplantation. There are also reports in the literature (Azetidine Based Transition State Analogue Inhibitors of N-Ribosyl Hydrolases and Phosphorylases. Journal of Medicinal Chemistry, 2008, Vol.51, No.4) that compounds 1-5 ( Figure 1 ) are all close analogues of pyrrolidine-3,4-diyl dimethanol (compound 6), which is an important intermediate for the synthesis of the low picomolar inhibitor DADMeimmucilin-H (7) of PNP.

[0003]

[0004] The synthesis method of the compound of formula I was reported in CN 113999239A: 5 g of the compound cis-5 (24.1 mmol, 1 eq.) was dissolved in 120 mL of ethanol, 0.9 g of Pd / C (10%) was added, the gas was displaced, hydrogen was charged, and the reaction was stirred at room temperature for 36 h. 7.9 g of (Boc)2O (36.2 mmol, 1.5 eq) and 6.1 g of sodium bicarbonate (72.3 mmol, 3 eq.) were added, and the reaction was continued at room temperature for 12 h. The mixture was filtered through diatomaceous earth, the filtrate was taken, dried over anhydrous sodium sulfate, concentrated under pressure, and 4.7 g of the compound cis-6 was obtained with a yield of 90%.

[0005]

[0006] A similar reaction route was also reported in WO 2008079028A1: The compound 27 (1.16 g, 5.60 mmol) was dissolved in EtOH (10 mL), di-tert-butyl dicarbonate (2.44 g, 11.2 mmol) was added, and then 20% Pd(OH)2 / C (200 mg) was added. The atmosphere was displaced with hydrogen by continuously applying vacuum, and then a hydrogen balloon was installed on the reaction vessel. The reaction mixture was stirred overnight, then the suspension was filtered through diatomaceous earth, the volatiles were removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (60:40 to 100:0 EtOAc / hexane) to obtain the compound 29 as a colorless oil (915 mg, yield 75%).

[0007]

[0008] In the prior art, methanol or ethanol is mostly used as a solvent in the synthesis of tert-butyl (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate (the compound of formula I), the consumption of palladium catalyst is large and the cost is high; in large-scale production, the traditional hydrogenation autoclave is highly dangerous, the reaction is difficult to control, and there may be emulsification problems during post-treatment. Therefore, it is necessary to develop a new process that is safe, stable, easy to operate, low-cost, and environmentally friendly. SUMMARY OF THE INVENTION

[0009] Object of the Invention: The object of the present invention is to overcome the problems of low reaction safety, high cost, and difficult post-treatment in the process of preparing tert-butyl (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate (Compound of Formula I) in the above-mentioned prior art, and provide an improved method for preparing tert-butyl (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate (Compound of Formula I): using green solvent water to replace methanol or ethanol as the solvent, selecting a suitable catalyst, adopting fixed-bed hydrogenation, and carrying out continuous reaction of the hydrogenation liquid and Boc anhydride in a flow reactor. After the reaction is completed, methyl tert-butyl ether is used as the extractant, and a centrifugal extractor is used for efficient continuous countercurrent extraction. The organic phase after extraction is directly desolvated with an evaporator, and finally diluted with acetonitrile to obtain an acetonitrile solution of the product. The present invention realizes the full continuity of the process from reaction to post-treatment through the modular combination of equipment such as continuous reactors, centrifugal extractors, and wiped film evaporators, effectively amplifies the production capacity and makes the product yield stable at a relatively high level (when the feeding amount is 80 kg, the yield can reach 95%), simplifies the post-treatment, reduces the cost of producing and treating three wastes, and is suitable for industrial production.

[0010]

[0011] A method for preparing a Compound of Formula I, characterized by comprising the following steps:

[0012]

[0013] Step 1: Dissolve the Compound of Formula II in water, and react with a reducing agent in a fixed-bed reactor under the catalytic action of a catalyst;

[0014] Step 2: React the reaction solution of Step 1 with an aqueous solution of Boc anhydride in a continuous reactor to form the Compound of Formula I.

[0015] Preferably, the catalyst in Step 1 is one of 15% Pd / C, 20% Pd / C, 20% Pd(OH)2 / C, or 5% Pd(OH)2 / Al2O3;

[0016] More preferably, the catalyst in Step 1 is 5% Pd(OH)2 / Al2O3.

[0017] Preferably, the reducing agent in Step 1 is hydrogen, and the flow rate in the fixed-bed reactor is 5 - 30 L / min.

[0018] Preferably, the reaction temperature in Step 1 is 50 - 100 °C, and the pressure of the reaction system is 2.0 - 3.0 Mpa.

[0019] Preferably, the molar ratio of the Compound of Formula II to Boc anhydride in Step 2 is 1:1 - 2;

[0020] More preferably, the molar ratio of the compound of Formula II to Boc anhydride in Step 2 is 1:1.1 to 1.5.

[0021] Preferably, the continuous reactor described in Step 2 is a tubular reactor.

[0022] Preferably, the reaction temperature in Step 2 is 15 - 25 °C; the feeding flow rate of the reaction solution in Step 1 is set at 600 - 800 mL / min, the feeding flow rate of the Boc anhydride aqueous solution is set at 300 - 500 mL / min, and the residence time is 5 - 30 min.

[0023] Preferably, after the reaction is completed, a continuous extractor is used for post-treatment, the extractant used is MTBE, and continuous multi-stage countercurrent extraction is carried out; the obtained organic phase is successively fed into a wiped film evaporator and a self-cleaning screw evaporator for continuous vacuum concentration of methyl tert-butyl ether; finally, acetonitrile is added to the self-cleaning screw evaporator, and after dissolution, an acetonitrile solution of the compound of Formula I is obtained.

[0024] Some of the reaction reagents involved in the present invention are abbreviated as follows:

[0025] MTBE: Methyl tert-butyl ether

[0026] Beneficial effects

[0027] The preparation method of tert-butyl (2R,4S)-2,4-bis(hydroxymethyl)azetidine-1-carboxylate (compound of Formula I) provided by the present invention mainly aims to reduce the industrial production cost and improve safety, stability, and simplify the post-treatment operation. Compared with traditional reactors such as high-pressure batch hydrogenation autoclaves, the continuous flow reactor can utilize its microchannel advantages to solve problems such as small gas-liquid-solid three-phase interface contact area and low interphase transfer rate. Its high-efficiency gas-liquid mass transfer efficiency and plug flow characteristics can also achieve highly selective deprotection and significantly shorten the reaction time. In addition, hydrogenation deprotection usually needs to be carried out under a certain pressure to increase the solubility of hydrogen in the solvent and its adsorption degree on the catalyst surface, so there is a certain operation risk. The fixed hydrogenation bed can achieve safe and controllable production purposes due to its advantages such as small volume, small liquid holdup, and low hydrogen retention. The original process used methanol as a solvent and reacted in a hydrogenation autoclave, with a large consumption of palladium catalyst, high cost, and high risk of traditional hydrogenation autoclaves, and the reaction was difficult to control. And directly using methanol as a solvent and treating it through a fixed hydrogenation bed would reduce the service life of the palladium catalyst, and the palladium catalyst would be deactivated after 24 h of reaction. The current process uses the green solvent water as a solvent and is treated through a fixed hydrogenation bed, and the activity of the palladium catalyst can be greatly improved.

[0028] In the post-treatment stage, continuous countercurrent extraction is achieved using a centrifugal extractant. A centrifugal extractor is a new type of fast and efficient liquid-liquid extraction and separation equipment. The centrifugal extractor uses an electric motor to drive the drum to rotate at a high speed. Two liquids with different densities and immiscible with each other complete mass transfer through mixing under the action of the shear force generated by the rotation of the drum or paddle blades, and are quickly separated under the action of the centrifugal force generated by the high-speed rotation of the drum. Compared with traditional kettle extraction, continuous countercurrent extraction has the following advantages. First, continuous countercurrent extraction has high efficiency, short residence time of the two phases, small retention volume, large throughput, and is easy to operate; traditional kettle extraction has low efficiency and long residence time of the two phases. Using continuous countercurrent extraction solvent also has the advantages of small consumption, small floor area of the equipment, and easy recovery and reuse of the solvent; while traditional kettle extraction has large solvent consumption, wide floor area of the equipment, and relatively high cost.

[0029]

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present invention.

[0032] Figure 1 It is the GC chromatogram of the control of the compound of Formula I in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] The following further clarifies the present invention in conjunction with specific embodiments. These embodiments are implemented on the premise of the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0034] Example 1

[0035]

[0036] Preparation of the compound of Formula I:

[0037] Ingredient preparation: Add process water (1192 kg) to the reaction kettle R1, start stirring, add the compound of Formula II (80 kg, 385.96 mol, 1 eq.), protect under N2 atmosphere, and control the temperature of the reaction kettle to 20 - 30 °C. Add process water (835.2 kg) and di-tert-butyl dicarbonate (92.8 kg, 425.2 mol, 1.1 eq.) to the reaction kettle R2, protect under N2 atmosphere, and control the temperature of the reaction kettle to 20 - 30 °C to obtain the Boc anhydride aqueous solution (B).

[0038] Add 5% Pd(OH)2 / Al2O3 catalyst to the micro-packed bed hydrogenation device until it is densely packed. Maintain the pressure at 1.5 - 3.0 Mpa, set the hydrogen flow rate at 15 - 30 L / min, set the jacket temperature of the preheater at 50 - 100 °C, set the jacket temperature of the reactor at 70 - 100 °C, set the liquid feed flow rate at 0.2 - 1.5 L / min, and run for 1 h to obtain the hydrogenation reaction liquid (A). Control the TCU temperature of the 10 L tubular reactor at 15 - 25 °C, set the feed flow rate of the hydrogenation reaction liquid (A) at 648 mL / min, set the feed flow rate of the Boc anhydride aqueous solution (B) at 352 mL / min, with a residence time of 10 min, and run stably for 0.5 h. Take an instantaneous sample for GC detection and the reaction is basically complete. The GC chromatogram is as Figure 1 shown. The qualified reaction liquid enters the continuous extractor through a peristaltic pump at a flow rate of 1 L / min, and the extractant MTBE enters from the other port at the same flow rate for continuous multi-stage countercurrent extraction. The obtained organic phase enters a wiped film evaporator and a self-cleaning screw evaporator in sequence for continuous vacuum concentration of methyl tert-butyl ether. Add acetonitrile to the self-cleaning screw evaporator, and after dissolution, an acetonitrile solution of the compound of formula I is obtained. The yield is calculated to be approximately 95% based on the content of the compound of formula I in the acetonitrile solution.

[0039] Although the specific embodiments of the present invention have been described above, it does not limit the protection scope of the present invention. For those of ordinary skill in the art in this technical field, without departing from the principle of the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that It comprises the following steps: Step 1: The compound of formula II is dissolved in water and reacts with a reducing agent under the catalysis of a catalyst in a fixed-bed reactor; Step 2: The reaction solution of Step 1 reacts with an aqueous solution of Boc anhydride in a continuous reactor to form the compound of formula I.

2. The preparation method according to claim 1, characterized in that: The catalyst described in Step 1 is one or more of 15% Pd / C, 20% Pd / C, 20% Pd(OH)2 / C or 5% Pd(OH)2 / Al2O3.

3. The preparation method according to claim 1, characterized in that: The catalyst described in Step 1 is 5% Pd(OH)2 / Al2O3.

4. The preparation method according to claim 1, characterized in that: The reducing agent described in Step 1 is hydrogen, and the flow rate in the fixed-bed reactor is 5 - 30 L / min.

5. The preparation method according to claim 1, characterized in that: The reaction temperature of Step 1 is 50 - 100 °C, and the pressure of the reaction system is 2.0 - 3.0 Mpa.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula II to Boc anhydride described in Step 2 is 1:1 - 2.

7. The preparation method according to claim 1, wherein: The molar ratio of the compound of formula II to Boc anhydride described in Step 2 is 1:1.1 - 1.

5.

8. The preparation method according to claim 1, characterized in that: The continuous reactor described in Step 2 is a tubular reactor.

9. The preparation method according to claim 1, characterized in that: The reaction temperature of Step 2 is 15 - 25 °C; the feed flow rate of the reaction solution of Step 1 is set at 600 - 800 mL / min, the feed flow rate of the aqueous solution of Boc anhydride is set at 300 - 500 mL / min, and the residence time is 5 - 30 min.

10. The preparation method according to claim 1, characterized in that: After the reaction is completed, during the post-treatment, a continuous extractor is used, and the extractant used is MTBE for continuous multi-stage countercurrent extraction; the obtained organic phase successively enters a wiped-film evaporator and a self-cleaning screw evaporator for continuous vacuum concentration of methyl tert-butyl ether; finally, acetonitrile is added to the self-cleaning screw evaporator, and after dissolution, an acetonitrile solution of the compound of formula I is obtained.

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