Continuous reaction device for preparing 5-hydroxy-7-azaindole

Abstract

The utility model discloses a continuous reaction device for preparing 5-hydroxy-7-azaindole. The continuous reaction device comprises a reaction tank, comprising a first knockout device, a second knockout device, a third gas feeding device, a fourth knockout device, an automatic feeding system, a mixer, a first plunger pump, a flowmeter, a first one-way valve, a back pressure valve, a first reaction coil pipe, a second reaction coil pipe, a third reaction coil pipe and a reaction kettle, the first knockout device is provided with a raw material A inlet, a solvent inlet and a mixed liquid outlet. The utility model develops a continuous synthesis process of 5-hydroxy-7-azaindole, a coil reactor is used, continuous feeding, continuous reaction and continuous transfer are carried out, the separation yield is more than 80% after post-treatment, and the efficient preparation of 5-hydroxy-7-azaindole is realized.

Description

TECHNICAL FIELD

[0001] The utility model relates to the field for technology field of pharmaceutical chemical industry, concretely is a kind of continuous reaction device for the preparation of 5-hydroxy-7-azaindole. BACKGROUND

[0002] ABT-199 (venetoclax), Venetoclax, also known as (venetoclax, Venclexta, Venetoclax, Venclyxto), is the world's first BCL-2 (B lymphocyte tumor-2 gene) inhibitor, a selective and a small-molecule inhibitor of an anti-apoptotic protein. It is significantly active in chronic lymphocytic leukemia, and is initially approved by FDA for chromosomal 17p deletion or relapsed / refractory chronic lymphocytic leukemia (CLL). And an important intermediate in the industrial production of Venetoclax is just 5-hydroxy-7-azaindole.

[0003] The existing preparation method of 5-hydroxy-7-azaindole usually takes 5-bromo-7-azaindole as raw material, protects the amino group, forms boronic acid at low temperature, and synthesizes the hydroxyl substituent by oxidative hydrolysis of the oxide, but this route needs to use organic lithium reagent, and the operation is not safe for amplification, the ultra-low temperature reaction requires high equipment, and the total yield is low.

[0004] Alternatively, 5-bromo-7-azaindole is used as raw material, sodium methoxide is used for methoxy substitution of bromine, and then demethylation is carried out to obtain hydroxyl product, but the amount of sodium methoxide used in this route is too large, and a lot of wastewater will be generated in post-processing, in addition, boron tribromide is volatile and toxic, and the post-processing is troublesome, which is not convenient for industrialization operation.

[0005] Alternatively, 5-bromo-7-azaindole is used as raw material, and Miyaura boronization reaction is carried out to prepare the corresponding boronic ester, and then hydroxyl product is obtained by hydrogen peroxide oxidation, but this reaction needs to use organic palladium catalyst, the cost is high, and there are a lot of double-molecule coupling products in the reaction, and the yield is low.

[0006] There is also a series of protecting groups to protect the amino group of indole, and then through copper-catalyzed Ullmann type carbon oxygen coupling, and finally deprotection to obtain 5-hydroxy-7-azaindole, but the protecting groups reported in the literature such as Tips, Boc, benzyl have many problems, such as Tips, Boc is not stable enough to withstand the subsequent strong Ullmann type carbon oxygen coupling reaction, and although benzyl can be tolerated, many methods such as hydrogenation reduction and oxidation debenzylation are difficult to remove. In order to overcome the above technical defects, the utility model discloses a kind of new 5-hydroxy-7-azaindole preparation device, by continuous reaction technology a kind of preparation 5-hydroxy-7-azaindole continuous oxygen oxidation synthesis process technology. The utility model develops a kind of 5-hydroxy-7-azaindole continuous synthesis process, uses coil reactor, continuous feeding, continuous reaction, continuous transfer, and more than 80% separation yield is obtained after post-treatment, and the efficient preparation of 5-hydroxy-7-azaindole is realized. Utility model content

[0007] The utility model discloses a kind of 5-hydroxy-7-azaindole preparation continuous reaction device, to solve the problems presented in the above background art.

[0008] To achieve the above object, the utility model provides the following technical scheme: a kind of 5-hydroxy-7-azaindole preparation continuous reaction device, including first material device, second material device, third gas feeding device, fourth material device, automatic feeding system, mixer, first plunger pump, flowmeter, first check valve, back pressure valve, first reaction coil, second reaction coil, third reaction coil and reaction kettle, first material device is provided with raw material A inlet and solvent inlet and mixed liquid outlet, second material device is provided with raw material B inlet and raw material B outlet, third gas feeding device is provided with steel bottle switching system, fourth material device is provided with raw material C inlet and raw material C outlet, simultaneously using automatic feeding system control first plunger pump, second plunger pump and third plunger pump and flowmeter to control the feeding rate of reaction, mixer, second mixer and third mixer are provided with feed inlet and reaction raw material outlet, first check valve and second check valve are respectively installed between second reaction coil and first mixer and second reaction coil and third mixer, and back pressure valve is arranged on conveying pipeline.

[0009] Preferably, first reaction coil and second reaction coil are provided with reaction raw material inlet and product system outlet, and reaction raw material inlet is connected with reaction raw material outlet and communicated through reaction raw material conveying pipeline.

[0010] Preferably, product system outlet is communicated with the inlet end of reaction kettle.

[0011] Compared with prior art, the utility model has the advantages of the following:

[0012] The utility model discloses a coil reactor is used, continuous feeding, continuous reaction, continuous transfer, and after posttreatment, more than 80% separation yield is obtained, and the efficient preparation of 5-hydroxy-7-azaindole is realized, and the 5-bromo-7-azaindole of amino protection is used as raw material, and the magnesium reagent of amino protection 5-bromo-7-azaindole is obtained by exchanging with magnesium reagent, and then, oxidation reaction occurs with oxygen, and then, the protecting group is hydrolyzed and removed, and the intermediate is not separated, and 5-hydroxy-7-azaindole is prepared efficiently, and the continuous equipment is used for the first time, and the 5-bromo-7-azaindole of amino protection is used as raw material, and 5-hydroxy-7-azaindole is prepared by continuous reaction, and the unit reaction time is shortened to 90min in the continuous reaction mode, and the contact time of product and metal reagent and oxygen is reduced, and the product is destroyed in the alkaline condition to the maximum extent, and the batch reaction is difficult to enlarge, and then, the continuous enlargement, and the industrial large-scale production is possible, and the separation yield is improved to 80% after the continuous process is enlarged, and the synthesis cost of the product is greatly reduced, and the use of continuous equipment reduces the risk coefficient of the use of active metal reagent and oxygen, and the manpower cost is also greatly saved, and it is beneficial to the industrial enlarged production, and the continuous reaction is relative to the traditional reaction, and the reaction can be stopped or terminated at any time according to the actual situation, and the posttreatment can be batched or combined according to the need, and it is convenient and simple. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 It is the main body structure schematic diagram of the utility model.

[0014] In the drawing: 10-first material device, 20-second material device, 30-third gas feeding device, 40-fourth material device, 50-automatic feeding system, 60-mixer, 70-first plunger pump, 80-flow meter, 90-first check valve, 100-back pressure valve, 110-first reaction coil, 120-reaction kettle, 71-second plunger pump, 72-third plunger pump, 61-second mixer, 62-third mixer, 111-second reaction coil, 91-second check valve, 112-third reaction coil. DETAILED DESCRIPTION

[0015] The technical scheme in the embodiments of the utility model will be apparently and completely described in combination with the drawings in the embodiments of the utility model, and apparently, the described embodiments are only part of the embodiments of the utility model, not all the embodiments. Based on the embodiments in the utility model, all other embodiments obtained by the person skilled in the art without creative labor belong to the range protected by the utility model.

[0016] Please refer to Figure 1The utility model provides an embodiment: a kind of 5-hydroxy-7-azaindole preparation's continuous reaction device, including first material device 10, second material device 20, third gas feeding device 30, fourth material device 40, automatic feeding system 50, mixer 60, first plunger pump 70, flowmeter 80, first check valve 90, back pressure valve 100, first reaction coil pipe 110, second reaction coil pipe 111, third reaction coil pipe 112 and reaction kettle 120, first material device 10 is provided with raw material A inlet and solvent inlet and mixed liquid outlet, second material device 20 is provided with raw material B inlet and raw material B outlet, third gas feeding device 30 is provided with steel bottle switching system, fourth material device 40 is provided with raw material C inlet and raw material C outlet, simultaneously using automatic feeding system 50 control first plunger pump 70, second plunger pump 71 and third plunger pump 72 and flowmeter 80 to control the feeding rate of reaction, mixer 60, second mixer 61 and third mixer 62 are provided with feed inlet and reaction raw material outlet, first check valve 90 and second check valve 91 are respectively installed between first reaction coil pipe 110 and second mixer 61 and second reaction coil pipe 111 and third mixer 62, and back pressure valve 100 is arranged on conveying pipeline.

[0017] First reaction coil pipe 110 and second reaction coil pipe 111 are provided with reaction raw material inlet and product system outlet, and reaction raw material inlet is communicated with reaction raw material outlet by reaction raw material conveying pipeline.

[0018] Product system outlet is communicated with the inlet end of reaction kettle 120.

[0019] Working principle: 1-TIPS-5-bromo-7-azaindole (265 g, 0.67 mol.) was dissolved in tetrahydrofuran (500 mL) to form a first solution; 2M isopropyl magnesium chloride tetrahydrofuran solution (400 ml, 0.8 mol.) was prepared to form a second solution; the first solution was pumped into a first coil of 60 mL, φ 3 mm in diameter, at a speed of 3.8 ml / min by pump A and the second solution was pumped into the coil at a speed of 2.2 ml / min by pump B, the coil was immersed in an ice water bath at -5 C±3 C, and the retention time was 10 min. The system flowing out of the first coil outlet entered a second coil of 120 ml, φ 3 mm in diameter, oxygen was passed in at a speed of 0.25 L / min, the coil was immersed in an ice water bath at -5 C±3 C, and the retention time was 20 min for oxidation reaction; the system flowing out of the second coil outlet entered a third coil of 480 ml, φ 6 mm in diameter, 36% hydrochloric acid (280 ml, 3.35 mol.) was prepared to form a fourth solution, which was pumped into the coil at a speed of 2 ml / min, the coil was immersed in a hot water bath at 45±3 C, and the retention time was 60 min for deprotection reaction. The outlet sample was measured by HPLC, and the system flowing out was quenched with sodium bicarbonate aqueous solution, separated and extracted, concentrated under reduced pressure, and then filtered after crystallization with ethyl acetate and n-heptane to obtain 5-hydroxy-7-azaindole 73.9 g, with a yield of 82.3%;

[0020] 1-Boc-5-bromo-7-azaindole (297 g, 1 mol.) was dissolved in tetrahydrofuran (750 mL) to form a first solution; 2M isopropyl magnesium bromide tetrahydrofuran solution (600 ml, 1.2 mol.) was prepared to form a second solution; the first solution was pumped into a first coil of 60 mL, φ 3 mm in diameter, at a speed of 3.8 ml / min by pump A and the second solution was pumped into the coil at a speed of 2.2 ml / min by pump B, the coil was immersed in an ice water bath at -5 C±3 C, and the retention time was 10 min. The system flowing out of the first coil outlet entered a second coil of 120 ml, φ 3 mm in diameter, oxygen was passed in at a speed of 0.25 L / min, the coil was immersed in an ice water bath at -5 C±3 C, and the retention time was 20 min for oxidation reaction; the system flowing out of the second coil outlet entered a third coil of 480 ml, φ 6 mm in diameter, 36% hydrochloric acid (417 ml, 5 mol.) was prepared to form a fourth solution, which was pumped into the coil at a speed of 2 ml / min, the coil was immersed in a hot water bath at 45±3 C, and the retention time was 60 min for deprotection reaction. The outlet sample was measured by HPLC, and the system flowing out was quenched with sodium bicarbonate aqueous solution, separated and extracted, concentrated under reduced pressure, and then filtered after crystallization with ethyl acetate and n-heptane to obtain 5-hydroxy-7-azaindole 113.3 g, with a yield of 84.5%;

[0021] The device is to use amino-protected 5-bromo-7-azaindole as raw material, through continuous reaction, exchange with magnesium reagent to get amino-protected 5-bromo-7-azaindole magnesium reagent, then oxidize with oxygen, and then hydrolyze to remove the protecting group, to efficiently prepare 5-hydroxy-7-azaindole. The protection device used includes but is not limited to: automatic feeding system, coil reactor, electronic scale, plunger pump, diaphragm pump, peristaltic pump, etc. In the continuous synthesis process, the amino-protected 5-bromo-7-azaindole is dissolved in an organic solvent to form a first solution, the magnesium reagent is dissolved in an organic solvent to form a second solution, the first solution and the second solution are mixed, and the 7-azaindole Grignard reagent 1 solution is obtained in the continuous reactor through the coil reactor. In the second stage, oxygen is used as the third feed to react with the 7-azaindole Grignard reagent 1 solution in the coil reactor to obtain intermediate 2. In the third stage, a strong protonic acid is prepared into a fourth solution, which is reacted with intermediate 2 in the coil reactor, and then treated to obtain 5-hydroxy-7-azaindole;

[0022] In the continuous synthesis method, the amino-protected 5-bromo-7-azaindole includes but is not limited to TIPS, Boc, MOM, BOM, etc. Preferably, TIPS and Boc are used.

[0023] In the continuous synthesis method, the organic solvent includes but is not limited to tetrahydrofuran, 2-methyltetrahydrofuran, n-butyl ether, ethylene glycol dimethyl ether, etc. Preferably, tetrahydrofuran is used.

[0024] In the continuous synthesis method, the magnesium reagent for hydrolyzing and removing the amino-protecting group includes but is not limited to methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride-lithium chloride, etc. Preferably, isopropyl magnesium chloride and isopropyl magnesium bromide are used.

[0025] In the continuous synthesis method, the molar ratio of amino-protected 5-bromo-7-azaindole: magnesium reagent: oxygen: strong protonic acid is selected from 1:(1.05-1.5):(2.5-5):(4-8), preferably 1:(1.1-1.2):(3-4):(5-6).

[0026] In the continuous synthesis method, the reaction temperature in the first stage is -70-20°C, preferably -10-10°C.

[0027] In the continuous synthesis method, the reaction temperature in the second stage is -20-10°C, preferably -10-0°C.

[0028] In the continuous synthesis method, the reaction temperature in the third stage is 20-90°C, preferably 40-50°C.

[0029] In the continuous synthesis method, the first solution is pumped into a first coil pipe with a volume of 60 mL and a diameter of φ3 mm at a speed of 3-5 ml / min by a pump, and the second solution is pumped into the first coil pipe at a speed of 2-3 ml / min by a pump, and the exchange reaction with the magnesium metal reagent is kept for 10 min; oxygen is introduced into a second coil pipe with a volume of 120 ml and a diameter of φ3 mm at a speed of 0.2-0.5 L / min after the exchange reaction, and the oxidation reaction is kept for 20 min; the fourth solution is pumped into a third coil pipe with a volume of 480 ml and a diameter of φ6 mm at a speed of 1-3 ml / min after the exchange reaction, and the deprotection reaction is kept for 60 min;

[0030] In the continuous synthesis method, the system flowing out is quenched with a sodium bicarbonate aqueous solution, and after liquid separation and extraction, the product is obtained by vacuum concentration, addition of ethyl acetate and n-heptane crystallization, and filtration.

[0031] Although the embodiments of the utility model have been shown and described, it can be understood by those skilled in the art that various changes, modifications, replacements and variations can be made to these embodiments without departing from the principles and spirits of the utility model, and the scope of the utility model is defined by the appended claims and their equivalents.

Claims

1. A continuous reaction apparatus for the preparation of 5-hydroxy-7-azaindole comprising a first dosing device (10), a second dosing device (20), a third gas feeding device (30), a fourth dosing device (40), an automatic feeding system (50), a mixer (60), a first piston pump (70), a flow meter (80), a first one-way valve (90), a back pressure valve (100), a first reaction coil (110), a second reaction coil (111), a third reaction coil (112) and a reactor (120), characterized in that: The first material mixing device (10) is provided with an inlet of raw material A, an inlet of solvent and an outlet of mixed liquid, the second material mixing device (20) is provided with an inlet of raw material B and an outlet of raw material B, the third gas feeding device (30) is provided with a cylinder switching system, the fourth material mixing device (40) is provided with an inlet of raw material C and an outlet of raw material C, and the automatic feeding system (50) is used to control the first plunger pump (70), the second plunger pump (71) and the third plunger pump (72) and the flow meter (80) to control the feeding rate of the reaction, the mixer (60), the second mixer (61) and the third mixer (62) are provided with feeding inlets and reaction raw material outlets, the first one-way valve (90) and the second one-way valve (91) are arranged between the first reaction coil (110) and the second mixer (61) and between the second reaction coil (111) and the third mixer (62) respectively, and the back pressure valve (100) is arranged on the conveying pipeline.

2. A continuous reaction apparatus for the preparation of 5-hydroxy-7- azaindole according to claim 1, characterized by the fact that: The first reaction coil (110) and the second reaction coil (111) are provided with reaction raw material inlets and product system outlets, and the reaction raw material inlets and the reaction raw material outlets are connected and communicated through a reaction raw material conveying pipeline.

3. A continuous reaction apparatus for the preparation of 5-hydroxy-7- azaindole according to claim 2, characterized in that: The product system outlet is connected and communicated with the inlet end of the reaction kettle (120).

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