Method for continuous high-concentration preparation of dotegravir

Abstract

The invention relates to a continuous preparation method of dotegravir DTG based on a micro-channel reactor, and particularly, the method comprises the following steps: carrying out DTG-I demethylation reaction on a DMF (Dimethyl Formamide) solution containing LiBr and DTG-I in the micro-channel reactor, intensifying mixing and reaction through an ultrasonic vibration rod, and carrying out continuous preparation on the dotegravir DTG through the micro-channel reactor. The problem of blockage caused by precipitation of an organic lithium intermediate in a micro-channel in the reaction process is prevented; the advantages of the micro-channel reactor are combined, and the DTG preparation yield is high and can reach 98.9%; the reaction time is shortened to 7 minutes; and the concentration of the reactant DTG-I can be increased to 0.9 mol / L.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals, and in particular discloses a method for synthesizing an anti-AIDS drug dolutegravir at a high concentration by using a continuous flow microchannel reactor. Background Art

[0002] Dolutegravir (DTG), trade name: Tivicay, is a second-generation integrase strand transfer inhibitor for the treatment of HIV-1 infection. It can prevent the transfer and integration of retroviral DNA chains. The drug was developed by GlaxoSmithKline and approved by the U.S. Food and Drug Administration in 2013.

[0003] Compared with the first-generation integrase strand transfer inhibitors including elvitegravir and raltegravir, DTG has the advantages of low dosage, higher resistance barrier and fewer side effects.

[0004] In the synthetic route, the intermediate product DTG-I after amidation undergoes a methyl ether demethylation reaction to obtain the product DTG. The reaction equation is as follows:

[0005]

[0006] In 2011, a Chinese patent (CN 102933080) disclosed a method for obtaining DTG by demethylating DTG-I using a Lewis acid magnesium halide or a lithium halide.

[0007] In the literature "7-step Flow synthesis of the HIV integrases inhibitor Dolutravir, 2018", an attempt was made to carry out a continuous reaction of the demethylation step of LiBr, but the study found that when the concentration of the product DTG in tetrahydrofuran was greater than 0.5M, pipeline blockage would occur, and this blockage problem was difficult to solve, resulting in the continuous operation time of the micro-reaction pipeline being no more than 10 hours.

[0008] Microchannel continuous reaction is a new technology developed in recent years. It has the advantages of safety, high efficiency, high quality and low cost. Specifically, it has the following characteristics: large specific surface area, high mass transfer and heat transfer efficiency, high heat exchange efficiency, high conversion rate and yield; reducing energy consumption while improving product selectivity; it can mix quickly and effectively, accurately control the reaction time, and is easy to scale up industrially.

[0009] The intermediate organic lithium generated in the demethylation step of the DTG synthesis process can cause blockage in the microchannel reactor. To avoid blockage, the concentration of the reaction solution can only be reduced, which has the disadvantages of large solvent consumption, energy-consuming and time-consuming concentration of the reaction solution in subsequent treatment, low reaction efficiency and excessively high cost.

[0010] In view of this, there is an urgent need to develop an efficient production process in this field to reduce the amount of solvent used, shorten the reaction time, and achieve continuous production of dolutegravir to meet the growing market demand for dolutegravir. Summary of the invention

[0011] An object of the present invention is to provide a method for the efficient and continuous production of dolutegravir.

[0012] The first aspect of the present invention provides a method for continuous production of dolutegravir, the method comprising:

[0013]

[0014] A mixed solution containing LiBr and DTG-I is provided, and a methyl ether demethylation reaction occurs in a microchannel reactor I under the action of ultrasound, and then the mixed solution reacts with an acetic acid solution in a microchannel reactor II to obtain DTG.

[0015] In another preferred embodiment, the microchannel reactor is a pipeline microchannel reactor or a plate microchannel reactor; preferably, it is a pipeline microchannel reactor.

[0016] In another preferred embodiment, the ultrasound is provided by an ultrasonic vibration rod.

[0017] In another preferred embodiment, the mixed solution containing DTG-I and LiBr enters a constant temperature oil bath (3) through a syringe pump (1) for heating, flows through a pipeline microchannel reactor I (4) under the ultrasonic action of an ultrasonic vibrator (5) to carry out a methyl ether demethylation reaction, and then flows through a T-type micromixer (6) and is mixed with an acetic acid solution transported by a syringe pump (2) in a pipeline microchannel reactor II (9) to undergo a neutralization reaction to produce DTG.

[0018] In another preferred embodiment, the constant temperature oil bath refers to reacting at a fixed reaction temperature.

[0019] In another preferred embodiment, the power of the ultrasound is 30-150W.

[0020] In another preferred embodiment, the inner diameter of the microchannel reactor is 0.5-10 mm; preferably 1-4 mm; more preferably 1-2 mm.

[0021] In another preferred embodiment, the material of the microchannel reactor is PFA, ETFE, FEP or glass.

[0022] In another preferred embodiment, the concentration of DTG-I in the mixed solution is 0.1-2 mol / L; preferably 0.4-1.5 mol / L; more preferably 0.4-1.0 mol / L.

[0023] In another preferred embodiment, the concentration ratio of LiBr to DTG-I in the mixed solution is 1-4; preferably 2-3; more preferably 2.

[0024] In another preferred embodiment, the flow rate of the mixed solution is 0.01-1 mL / min; preferably 0.1-1 mL / min; more preferably 0.1-0.4 mL / min.

[0025] In another preferred embodiment, the concentration of the acetic acid solution is 0.2-4 mol / L; preferably 0.5-2 mol / L; more preferably 0.5-1 mol / L.

[0026] In another preferred embodiment, the reaction temperature in the microchannel reactor I is 100-170°C; preferably 120-160°C; more preferably 140-150°C.

[0027] In another preferred embodiment, the reaction temperature in the microchannel reactor II is room temperature; preferably 10-40°C; more preferably 15-30°C.

[0028] In another preferred embodiment, the ratio of the concentration of DTG-I to the inner diameter of the microchannel reactor ((mol / L) / mm) is 0.2-0.6; preferably 0.4-0.5.

[0029] In another preferred embodiment, the ratio of the concentration of DTG-I to the flow rate of the mixed solution is 2-6; preferably 3-5.

[0030] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Schematic diagram of the structure of the continuous production device; wherein 1 is a syringe pump, 2 is a syringe pump, 3 is a constant temperature oil bath, 4 is a pipeline microchannel reactor I, 5 is an ultrasonic vibrator, 6 is a T-type micro mixer, 7 is a constant temperature water bath, 8 is a conical flask, 9 is a pipeline microchannel reactor II, and 10 is a back pressure valve;

[0032] Figure 2 Schematic diagram of the effect of reaction temperature on the synthesis of DTG in a microchannel reactor;

[0033] Figure 3 Schematic diagram of the effect of the concentration of raw material DTG-I on the synthesis of DTG in a microchannel reactor;

[0034] Figure 4 Schematic diagram of the effect of LiBr concentration on the synthesis of DTG in a microchannel reactor. DETAILED DESCRIPTION

[0035] After extensive and in-depth research, the inventors have provided a new method for preparing dolutegravir for the first time. In the method of the present invention, a microchannel reactor is used to enhance the mass and heat transfer of reactants, and ultrasonic technology is used to avoid pipeline blockage; at the same time, the method of the present invention can use high-concentration reactants, reduce solvent consumption, save reaction time, reduce costs, and also have high reaction efficiency. Based on this, the inventors have completed the present invention.

[0036] Highly efficient and continuous production process of dolutegravir

[0037] Since the kettle reaction process for preparing dolutegravir in the prior art has a long reaction time and low yield, the applicant has proposed a new method for preparing DTG by demethylating high-concentration DTG-I methyl ether in a continuous flow microchannel.

[0038] The specific process is as follows:

[0039] According to the present invention, a reaction liquid (1) containing DTG-I and LiBr enters a constant temperature oil bath (3) through an injection pump (1) for heating, flows through a pipeline microchannel reactor I (4) under the ultrasonic action of an ultrasonic vibrating rod (5) to carry out a methyl ether demethylation reaction, then flows through a T-type micro mixer (6) and is mixed with an acetic acid solution pumped in through an injection pump (2) in a pipeline microchannel reactor II (9) to produce DTG through a neutralization reaction.

[0040] The microchannel reactor comprises: a pipeline microchannel or a plate microchannel, the output end of the reactor is connected to a conical flask, and the input end injects the reaction liquid into the microchannel reactor through a horizontal flow pump or a syringe pump.

[0041] The inner diameters of the microchannel reactor I and the microchannel reactor II are the same, which is 0.5-10 mm; preferably 1-4 mm; more preferably 1-2 mm.

[0042] The concentration of DTG-I in the mixed solution is 0.1-2 mol / L; preferably 0.4-1.5 mol / L; more preferably 0.4-1.0 mol / L.

[0043] The inner diameter of the microchannel reactor is 0.5-10 mm and is made of materials such as PFA, ETFE, FEP and glass.

[0044] The ultrasound of the present application can be provided by any ultrasound equipment in the art. Preferably, the ultrasound of the present invention is provided by an ultrasonic vibration rod. Specifically, the power of the ultrasound is 30 to 150W.

[0045] The flow rate of the mixed solution is 0.01-1 mL / min; preferably 0.1-1 mL / min; more preferably 0.1-0.4 mL / min.

[0046] The concentration of the acetic acid solution is 0.2-4 mol / L, preferably 0.5-2 mol / L, and more preferably 0.5-1 mol / L.

[0047] The oil bath heating temperature (microchannel reactor I) is 100-170°C; preferably 120-160°C; more preferably 140-150°C.

[0048] In one embodiment, the ratio of the concentration of DTG-I to the inner diameter of the microchannel reactor is 0.2-0.6; preferably 0.4-0.5.

[0049] In one embodiment, the microchannel is used equivalently to a microchannel reactor.

[0050] In another embodiment, the ratio of the concentration of DTG-I to the flow rate of the reaction solution is 2-6; preferably 4-5.

[0051] Compared with the prior art, the main advantages of the present invention include:

[0052] (a) The method of the present invention allows the reaction to be carried out in a microchannel reactor at a high reactant concentration without causing microchannel blockage.

[0053] (b) The method of the present invention has a high selectivity for DTG, which can reach 99%.

[0054] (c) Using ultrasound to make high concentration reactants react and improve reaction efficiency.

[0055] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the following examples without specifying specific conditions are based on the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0056] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0057] Examples 1-4

[0058] The performance of the reaction of demethylating DTG-I methyl ether to prepare DTG in different solvents was tested.

[0059] The steps are as follows: After the continuous production device system is checked and sealed, dolutegravir intermediate DTG-I and LiBr are used as raw materials, THF, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) and acetonitrile (CH 3 CN) as solvent, the reaction temperature is 60°C. The reaction liquid enters the constant temperature oil bath (3) through the injection pump (1) for heating. Under the ultrasonic action of the ultrasonic vibrator (5), the reaction liquid flows through the pipeline microchannel reactor I (4) to carry out methyl ether demethylation reaction for 20 minutes. The ultrasonic vibrator power is 0W. Then it flows through the T-type micro mixer (6) and mixes with the acetic acid solution pumped in by the injection pump (2) in the pipeline microchannel reactor II (9). The neutralization reaction takes place for 2 minutes to obtain DTG. After the reaction for 60 minutes, the collected liquid is sampled and analyzed. The analysis results are shown in Table 1 (wherein, the conversion rate refers to the conversion rate of DTG-I, and the yield refers to the yield of DTG).

[0060] Wherein, the microchannel reactor is a pipeline microchannel.

[0061] The inner diameter of the pipeline microchannel is 1 mm and is made of PFA material.

[0062] The pipeline microchannel is connected to a fluid pump to control the liquid flow rate at 0.1 mL / min;

[0063] The concentration of DTG-I in the reaction system was 0.3 mol / L;

[0064] The concentration of LiBr in the reaction system is 0.6 mol / L;

[0065] The concentration of acetic acid in the reaction system is 0.8 mol / L;

[0066] The concentration of DTG-I and the concentration of DTG were determined by liquid chromatography (HPLC).

[0067] Table 1 Performance evaluation of DTG reaction prepared by different solvents

[0068]

[0069] As shown in Table 1, among the above solvents, the solubility of the intermediate organolithium of DTG-I demethylation in DMF is the highest.

[0070] The present invention uses DMF as solvent in the following examples to avoid blockage caused by precipitation of the intermediate organic lithium in the microchannel I during demethylation.

[0071] Example 5

[0072] The performance of the DTG-I demethylation to DTG reaction at different reaction temperatures was tested.

[0073] In this embodiment, a constant temperature oil bath is used to control the temperature at 120-150° C., the concentration of DTG-I is 0.3 mol / L, the concentration of LiBr is 0.6 mol / L, the flow rate of the reaction solution is controlled at 0.1 mL / min, and the inner diameter of the microchannel reactor is 1.0 mm.

[0074] The reaction solution containing DTG-I and LiBr is introduced into a constant temperature oil bath (3) through a syringe pump (2) via a syringe (1) for heating. Under the ultrasonic action of an ultrasonic vibrator (5), the reaction solution flows through a pipeline microchannel reactor I (4) for methyl ether demethylation reaction for 5 minutes. The ultrasonic vibrator power is 0 W. The reaction solution then flows through a T-type micromixer (6) and is mixed with acetic acid solution in a pipeline microchannel reactor II (9) for a neutralization reaction for 2 minutes to obtain DTG. After the reaction lasts for 21 minutes, the collected liquid is sampled and analyzed.

[0075] like Figure 2 As shown in the figure, when the reaction temperature increases from 120°C to 150°C, the conversion rate of the raw material DTG-I increases rapidly, and the selectivity of the product DTG is maintained above 99%. When the reaction temperature is 150°C, the conversion rate of DTG-I can be increased to 78.7%. When the reaction temperature continues to increase to 160°C, the selectivity of the product DTG-I decreases due to the ring-opening side reaction.

[0076] Considering the reaction rate and selectivity, the optimal temperature for the demethylation of DTG-I to prepare DTG is 150℃.

[0077] Example 6

[0078] Compare the performance evaluation of the DTG-I demethylation reaction to prepare DTG at different DTG-I concentrations.

[0079] In this embodiment, a constant temperature oil bath (3) is used to control the temperature at 150°C, the molar ratio of LiBr to DTG-I is 2, the flow rate of the reaction solution is controlled to be 0.1 mL / min, the inner diameter of the microchannel reactor is 1.0 mm, the power of the ultrasonic vibrator is 0 W, and the concentrations of DTG-I are 0.1, 0.2, 0.25, 0.3 and 0.4 mol / L, respectively.

[0080] The reaction liquid containing DTG-I and LiBr enters a constant temperature oil bath (3) through a syringe pump (1) for heating, and flows through a pipeline microchannel reactor I (4) under the ultrasonic action of an ultrasonic vibrator (5) to carry out a methyl ether demethylation reaction for 5 minutes, with the ultrasonic vibrator power being 0 W. The reaction liquid then flows through a T-type micromixer (6) and is mixed with the acetic acid solution pumped in through a syringe pump (2) in a pipeline microchannel reactor II (9) for a neutralization reaction for 2 minutes to obtain DTG. After the reaction lasts for 21 minutes, the collected liquid is sampled for analysis.

[0081] It can be seen that in the absence of ultrasound, with DMF as the solvent, the maximum concentration of DTG-I that can be used is 0.4 mol / L. Exceeding this concentration will cause blockage of the microchannel.

[0082] like Figure 3 As shown in the figure, with the increase of DTG-I concentration, the conversion rate of DTG-I increased rapidly under the same reaction time, and the selectivity of the product DTG was maintained above 99%. When the DTG-I concentration increased to 0.4 mol / L, the conversion rate of DTG-I could be increased to 98.9%.

[0083] As the concentration of DTG-I continued to increase, solid organic lithium precipitated in the microchannel reactor and caused blockage. Therefore, the optimal concentration of DTG-I was 0.4 mol / L without ultrasound.

[0084] Example 7

[0085] The performance evaluation of the demethylation reaction of DTG-I to prepare DTG was compared with different LiBr concentrations.

[0086] In this embodiment, a constant temperature oil bath (3) is used to control the temperature at 150°C, the concentration of DTG-I is 0.4 mol / L, the power of the ultrasonic vibrator is 0 W, the molar ratios of LiBr to DTG-I are 1, 1.2, 1.4, 1.6 and 2 respectively, the flow rate of the reaction liquid is controlled at 0.1 mL / min, and the inner diameter of the microchannel reactor is 1.0 mm.

[0087] Due to the solubility limitation of solid DTG-I and LiBr in solvent DMF, when the concentration of DTG-I is 0.4 mol / L and the molar ratio of LiBr to DTG-I exceeds 2, solid will precipitate in the raw material solution and the experiment cannot be carried out.

[0088] The reaction solution containing DTG-I and LiBr is introduced into a constant temperature oil bath (3) through a syringe pump (2) via a syringe (1) for heating. Under the ultrasonic action of an ultrasonic vibrator (5), the reaction solution flows through a pipeline microchannel reactor I (4) for methyl ether demethylation reaction for 5 minutes. The ultrasonic vibrator power is 0 W. The reaction solution then flows through a T-type micromixer (6) and is mixed with acetic acid solution in a pipeline microchannel reactor II (9) for a neutralization reaction for 2 minutes to obtain DTG. After the reaction lasts for 21 minutes, the collected liquid is sampled for analysis.

[0089] like Figure 4 As shown in the figure, with the increase of LiBr concentration, the conversion rate of DTG-I increased rapidly under the same reaction time, and the selectivity of the product DTG was maintained above 99%. When the molar ratio of LiBr to DTG-I increased to 2, the conversion rate of DTG-I could be increased to 98.9% after 5 minutes of reaction.

[0090] Under the reaction conditions without ultrasonic enhancement, the maximum concentration of DTG-I in the microchannel reactor is 0.4 mol / L. When the molar ratio of LiBr to DTG-I is 2, the reaction temperature is 150°C, and the reaction time of the demethylation reaction is 5 min, the conversion rate of the raw material DTG-I is 98.9% and the selectivity of the product DTG is 99%.

[0091] Example 8

[0092] DTG was prepared by high concentration method under the intensification of ultrasonic vibration rod.

[0093] In this embodiment, a constant temperature oil bath (3) is used to control the temperature at 150°C, the concentration of DTG-I is 0.8 mol / L, the molar ratio of LiBr to DTG-I is 2, the flow rate of the reaction solution is controlled at 0.2 mL / min, and the inner diameter of the microchannel reactor is 2.0 mm. It can be clearly observed that white solid precipitates in the microchannel at this reaction concentration.

[0094] The reaction solution containing DTG-I and LiBr is introduced into a constant temperature oil bath (3) through a syringe pump (2) via a syringe (1) for heating. Under the ultrasonic action of an ultrasonic vibrator (5), the reaction solution flows through a pipeline microchannel reactor I (4) to undergo a methyl ether demethylation reaction for 5 minutes. The reaction solution then flows through a T-type micromixer (6) and is mixed with an acetic acid solution in a pipeline microchannel reactor II (9) for a neutralization reaction for 2 minutes to obtain DTG. After the reaction lasts for 21 minutes, the collected liquid is sampled for analysis.

[0095] When the power of the ultrasonic vibrator is lower than 30W, there is blockage in the microchannel and the reaction cannot proceed normally; when the power of the ultrasonic vibrator is 30W, there is no blockage in the microchannel and the DTG-I demethylation reaction can continue.

[0096] With the strengthening of the microchannel reactor by the ultrasonic vibrator, when the power of the ultrasonic vibrator is 30W, the concentration of the raw material DTG-I in the microchannel where the demethylation reaction proceeds normally increases from 0.4mol / L to 0.8mol / L, the selectivity of the product DTG is maintained above 99%, and the yield of DTG is 98.5%.

[0097] Example 9

[0098] DTG was prepared by increasing the power of the ultrasonic vibrator at a high concentration.

[0099] In this embodiment, a constant temperature oil bath (3) is used to control the temperature at 150°C, the concentration of DTG-I is 0.9 mol / L, the power of the ultrasonic vibrator is 150 W, the molar ratio of LiBr to DTG-I is 2, the flow rate of the reaction solution is controlled at 0.2 mL / min, and the inner diameter of the microchannel is 2.0 mm.

[0100] The reaction solution containing DTG-I and LiBr is introduced into a constant temperature oil bath (3) through a syringe pump (2) via a syringe (1) for heating. Under the ultrasonic action of an ultrasonic vibrator (5), the reaction solution flows through a pipeline microchannel reactor I (4) to undergo a methyl ether demethylation reaction for 5 minutes. The reaction solution then flows through a T-type micromixer (6) and is mixed with an acetic acid solution in a pipeline microchannel reactor II (9) for a neutralization reaction for 2 minutes to obtain DTG. After the reaction lasts for 21 minutes, the collected liquid is sampled for analysis.

[0101] With the increase of ultrasonic vibrator power, when DTG was prepared normally and continuously in the microchannel reactor, the maximum concentration of raw material DTG-I increased from 0.8 mol / L to 0.9 mol / L, the selectivity of product DTG was maintained above 99%, and the yield of DTG was 99%.

[0102] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for continuous production of dolutegravir, characterized in that: The method includes: A mixed solution containing LiBr and DTG-I is provided, and a methyl ether demethylation reaction occurs in a microchannel reactor I under the action of ultrasound, and then reacts with an acetic acid solution in a microchannel reactor II to obtain DTG.

2. The method according to claim 1, characterized in that The mixed solution containing DTG-I and LiBr enters an oil bath (3) through a syringe pump (1) for heating, flows through a pipeline microchannel reactor I (4) under the ultrasonic action of an ultrasonic vibrator (5) to undergo a methyl ether demethylation reaction, then flows through a T-type micromixer (6) and is mixed with an acetic acid solution transported by a syringe pump (2) in a pipeline microchannel reactor II (9) to undergo a neutralization reaction to produce DTG.

3. The method according to claim 1, characterized in that The concentration of DTG-I in the mixed solution is 0.1-2 mol / L; preferably 0.2-1 mol / L; more preferably 0.4-0.8 mol / L.

4. The method according to claim 1, characterized in that The ratio of the concentration of DTG-I to the inner diameter of the microchannel reactor I ((mol / L) / mm) is 0.2-0.6; preferably 0.4-0.

5.

5. The method according to claim 1, characterized in that The power of the ultrasound is 30-150W.

6. The method according to claim 1, characterized in that The inner diameters of the microchannel reactors I and II are both 0.5-10 mm, preferably 1-4 mm, and more preferably 1-2 mm.

7. The method according to claim 1, characterized in that The concentration ratio of LiBr to DTG-I in the mixed solution is 1-4; preferably 2-3; more preferably 2.

8. The method according to claim 1, characterized in that The flow rate of the mixed solution is 0.01-1 mL / min; preferably 0.1-1 mL / min; more preferably 0.1-0.4 mL / min.

9. The method according to claim 1, characterized in that The concentration of the acetic acid solution is 0.2-4 mol / L, preferably 0.5-2 mol / L, and more preferably 0.5-1 mol / L.

10. The method according to claim 1, characterized in that The reaction temperature in the microchannel reactor I is 100-170°C; preferably 120-160°C; more preferably 140-150°C.

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