Method for fully continuously synthesizing mGlu2 / 3 negative allosteric regulator MNI-137 based on microreactor

Abstract

The invention discloses a fully continuous synthesis method of MNI-137, which comprises the following steps: mixing an organic metal reagent solution with an ethyl acetate solution, and reacting I in a first microchannel reactor to obtain an enol intermediate; mixing the enol intermediate with a 2-cyano-4-methyl picolinate solution, carrying out a reaction II in a second microchannel reactor, and carrying out acid quenching and separation to obtain an organic phase; mixing the organic phase with a 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution, and carrying out a reaction III in a third microchannel reactor to obtain an intermediate; mixing the intermediate with a trifluoroacetic acid solution, and carrying out a reaction IV in a fourth microchannel reactor to obtain MNI-137; the organic metal reagent is selected from at least one of lithium methide, n-butyllithium, sec-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and potassium tert-butoxide.

Description

Technical Field

[0001] The present application relates to a method for the fully continuous synthesis of the mGlu2 / 3 negative allosteric regulator MNI-137 based on a microreactor, and belongs to the pharmaceutical field. Background Art

[0002] MNI-137 (Chinese name: 4-(8-bromo-2,3-dihydro-2-oxo-1H-1,5-benzodiazepine-4-yl)-2-pyridinecarbonitrile, CAS number: 946619-21-2) is a selective negative allosteric modulator of class II mGlu receptors. It negatively regulates the activity of adenylate cyclase by coupling with Gi / o proteins and is used in biochemistry, medical experiments and other fields.

[0003] The existing synthesis method for MNI-137 starts from 2-cyano-4-pyridine acid methyl ester, and after cross-ester condensation with tert-butyl acetate, it is prepared by amidation, amide deprotection-cyclization three-step reaction. Cosford et al. [Tetrahedron, 2018, vol 74, p.3165-3170] reported a preparation method based on a microreactor, using a microreactor for cross-ester condensation, realizing the change of the condensation reaction conditions of 2-cyano-4-pyridine acid methyl ester and tert-butyl acetate from ultra-low temperature -78°C to -30°C, and obtaining the cross-ester condensation product by column chromatography with a yield of 66%, followed by amidation, amide deprotection-cyclization three-step preparation. This process uses sterically hindered tert-butyl acetate and 2-cyano-4-pyridinic acid methyl ester for cross-ester condensation. Although the reaction conditions are milder than the original ultra-low temperature conditions, the process involves column chromatography purification of intermediates, which greatly increases the separation process and post-processing costs of industrial production. In addition, the cross-ester condensation yield is low, and the introduction of large steric hinderance groups leads to a slow rate of the next amidation reaction, which also greatly prolongs the reaction time. Therefore, this synthetic route has many defects and is difficult to carry out continuous, efficient and rapid synthesis. Summary of the invention

[0004] The present invention uses the advantages of microreactors in mixing, mass transfer and heat transfer, and uses small steric hindrance ethyl acetate and 2-cyano-4-pyridine acid methyl ester for cross-ester condensation, which not only changes the reaction temperature from -78°C to room temperature 20°C, but also greatly improves the yield of the synthesis; through the quenching process design, the present invention realizes continuous online separation of the cross-ester condensation product, thereby avoiding the column chromatography purification process, greatly reducing the post-processing process time and cost; by using small steric ester coupling, the amidation reaction time is greatly reduced; the three-step synthesis process realizes continuous production based on microreactors, and the total yield of the product MNI-137 reaches 86%, and the purity is greater than 99% (HPLC characterization); the total residence time only needs 20 minutes. This invention provides an industrial route for continuous, efficient and rapid synthesis of MNI-137.

[0005] The purpose of the present invention is to realize the full continuous synthesis of mGlu2 / 3 negative allosteric regulator MNI-137 based on the remarkable advantages of microreactor in mixing, mass transfer and heat transfer.

[0006] To achieve the above objectives, a microreactor-based fully continuous synthesis process for the mGlu2 / 3 negative allosteric modulator MNI-137 is provided, which includes a three-step reaction of cross-ester condensation of 2-cyano-4-pyridine acid methyl ester and ethyl acetate mediated by an organometallic lithium reagent, amidation, and deprotection-cyclization.

[0007] According to one aspect of the present application, a method for the full continuous synthesis of MNI-137 is provided, comprising the following steps:

[0008] The organic metal reagent solution is mixed with the ethyl acetate solution, and reacted in a first microchannel reactor to obtain an enol intermediate;

[0009] The enol intermediate is mixed with 2-cyano-4-pyridine acid methyl ester solution, reacted in a second microchannel reactor, quenched with acid, and separated to obtain an organic phase;

[0010] The organic phase is mixed with a 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution, and reacted in a third microchannel reactor to obtain an intermediate.

[0011] The intermediate is mixed with a trifluoroacetic acid solution, and reacted in a fourth microchannel reactor to obtain MNI-137;

[0012] The organometallic reagent is selected from at least one of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide and potassium tert-butoxide.

[0013] The solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, n-hexane, cyclohexane and n-heptane;

[0014] The solvent in the ethyl acetate solution, 2-cyano-4-pyridine acid methyl ester solution, 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution and trifluoroacetic acid solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane and n-heptane.

[0015] The acid is selected from at least one of dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid, citric acid, sodium citrate-citric acid buffer solution, acetic acid, trifluoroacetic acid, and ammonium chloride-dilute hydrochloric acid solution;

[0016] The concentration of the acid is 0.5 to 3 mol / L;

[0017] The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium hydrogen carbonate, and the concentration is saturated.

[0018] The molar ratio of the organic metal reagent solution to ethyl acetate is 2 to 2.6:1;

[0019] The temperature of the reaction I is -20 to 20°C;

[0020] The reaction time is 1 second to 3 minutes.

[0021] The molar ratio of 2-cyano-4-pyridinic acid methyl ester to ethyl acetate is 1:1-2;

[0022] The temperature of the reaction II is -20 to 20°C;

[0023] The reaction time of the reaction II is 1s to 3min;

[0024] The quenching temperature is 0-20°C.

[0025] The molar ratio of the 1-Boc protected amino-2-amino-4-bromobenzene to triethylamine is 1:1 to 1.6;

[0026] The molar ratio of the organic phase to 1-Boc protected amino-2-amino-4-bromobenzene is 1:1 to 1.6;

[0027] The temperature of the reaction III is 0 to 40°C;

[0028] The time of the reaction III is 5 to 10 minutes.

[0029] The molar ratio of the intermediate to trifluoroacetic acid is 1:10-20;

[0030] The temperature of the reaction IV is 0 to 40°C;

[0031] The time of the reaction IV is 15 to 30 minutes.

[0032] The first microchannel reactor, the second microchannel reactor, the third microchannel reactor, and the fourth microchannel reactor are connected in sequence;

[0033] The hydraulic diameters of the first microchannel reactor, the second microchannel reactor, the third microchannel reactor and the fourth microchannel reactor are 100 μm to 10 mm.

[0034] The specific steps are as follows:

[0035] (1) Cross-ester condensation reaction mediated by organometallic lithium reagents;

[0036] The organic metal lithium reagent solution and the ethyl acetate solution are pumped into the first microchannel reactor at a certain flow rate and a certain ratio, and reacted at a certain temperature for a certain time to generate a lithium enolate intermediate; then the lithium enolate intermediate and the 2-cyano-4-pyridine acid methyl ester solution are pumped into the second microchannel reactor at a certain flow rate and a certain ratio, and reacted at a certain temperature for a certain time to generate product 2;

[0037] (2) Quenching reaction of cross-ester condensation;

[0038] The enolate of intermediate 2 generated in step (1) is passed into a quenching kettle and quenched with an acid-containing aqueous solution at a certain temperature to generate a stable intermediate 2 product;

[0039] (3) Amidation reaction;

[0040] The upper organic phase after quenching in step (2) and the 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution are pumped into the third microchannel reactor at a certain flow rate and a certain ratio, and reacted at a certain temperature for a certain time to generate product 3;

[0041] (4) Deprotection-cyclization reaction;

[0042] The intermediate 3 solution obtained in step (3) and the trifluoroacetic acid solution are pumped into the fourth microchannel reactor at a certain flow rate and a certain ratio, and reacted at a certain temperature for a certain time to generate the product MNI-137.

[0043] The beneficial effects of this application include:

[0044] The present invention innovatively proposes a fully continuous synthesis process of mGlu2 / 3 negative allosteric modulator MNI-137 based on a microreactor, including a three-step reaction of cross-ester condensation of 2-cyano-4-pyridine acid methyl ester and ethyl acetate mediated by an organometallic lithium reagent, amidation and deprotection-cyclization. Compared with the traditional synthesis route based on a kettle process, the present invention develops a cross-ester condensation of small sterically hindered ethyl acetate and 2-cyano-4-pyridine acid methyl ester based on a microreactor, thereby greatly improving the amidation reaction rate of the second step and shortening the time required for the second step amidation reaction; in addition, based on the mixing and mass transfer and heat transfer advantages of the microreactor, the molar ratio of the two types of esters in the cross-ester condensation is close to 1, and it can be carried out efficiently at room temperature, which greatly reduces the generation of self-condensation products and reduces the possibility of self-condensation products in the second step reaction for amidation; in the three-step reaction, by designing the process connection method, the intermediate can efficiently enter the next step reaction without any treatment. The total yield of the three-step synthesis of MNI-137 is 86%, and the purity of the product MNI-137 is greater than 99% (HPLC characterization). The total residence time of the process route only requires 20 minutes, and there is no time for intermediate purification, which realizes continuous and efficient production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is a schematic diagram of the device used in Example 1.

[0046] N2 Gas-nitrogen gas storage tank; 1: organic metal lithium reagent storage tank; 2: ethyl acetate solution storage tank; 3: 2-cyano-4-pyridine acid methyl ester solution storage tank; 4: quenching liquid storage tank; 5: quenching kettle; 6: 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution storage tank; 7: trifluoroacetic acid solution storage tank; R1: the first microchannel reactor; R2: the second microchannel reactor; R3: the third microchannel reactor; R4: the fourth microchannel reactor. DETAILED DESCRIPTION

[0047] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0048] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0049] Example 1

[0050] use Figure 1The device shown; before the reaction starts, a specific concentration of organic metal lithium reagent solution is pre-prepared, and the organic metal lithium reagent solution storage tank is stored at 0°C. Open the nitrogen storage tank, and introduce nitrogen into the reaction system for 10 minutes to replace the air in the system. After the pressure in the system is stable, open the storage tank 2 containing 1mol / L ethyl acetate solution and the storage tank 1 containing 2mol / L diisopropyl lithium amide, set the flow rate of the horizontal flow pump to 10ml / min, and pump the two raw material liquids into the first microchannel reactor; after the operation is stable, open the storage tank 3 containing 1mol / L 2-cyano-4-pyridine acid methyl ester solution, set the flow rate of the horizontal flow pump to 10ml / min; set the residence time in the first microchannel reactor to 1min, and the residence time in the second microchannel reactor to 1min, and the reaction is operated at 20°C to generate intermediate 2 throughout the process; after the operation is stable, open the quenching liquid storage tank, set the flow rate of the horizontal flow pump to 30ml / min, and the reaction solution and the quenching liquid are mixed and then enter the quenching tank and quenched at 20°C; the upper organic phase is mixed with 1.2mol / L 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution was pumped into the third microchannel at a flow rate of 30 ml / min to react to generate intermediate 3, which was reacted at 40°C for 5 min; 5 mol / L trifluoroacetic acid solution was pumped into the fourth microchannel reactor together with intermediate 3 at a flow rate of 10 ml / min, and reacted at 40°C for 10 min to obtain a product solution containing MNI-137. Pure MNI-137 yellow solid was obtained by recrystallization operation, with a weighed yield of 86%. Its purity was greater than 99% monitored by HPLC.

[0051] Example 2

[0052] The specific reaction process is similar to that of Example 1. The residence time in the first microchannel reactor is 30 s, and the reaction is carried out at 20° C. After the three-step reaction is completed, MNI-137 yellow solid is obtained by recrystallization, with a weighed yield of 46%. The purity thereof is greater than 99% as monitored by HPLC.

[0053] Example 3

[0054] The specific reaction process is similar to that of Example 1. The residence time in the first microchannel reactor is 1 min, and the reaction is carried out at 0° C. After the three-step reaction is completed, MNI-137 yellow solid is obtained by recrystallization, with a weighed yield of 84% and a purity greater than 99% monitored by HPLC.

[0055] Example 4

[0056] The specific reaction process is similar to that of Example 1, the concentration of lithium diisopropylamide solution is 0.5 mol / L, and after the three-step reaction, MNI-137 yellow solid is obtained by recrystallization, with a weighed yield of 29% and a purity greater than 80% as monitored by HPLC.

[0057] Example 5

[0058] The specific reaction process is similar to that of Example 1. The concentration of 2-cyano-4-pyridine acid methyl ester solution is 0.5 mol / L. After the three-step reaction, MNI-137 yellow solid is obtained by recrystallization. The weighed yield is 73%. The purity is greater than 90% under HPLC monitoring.

[0059] Example 6

[0060] The specific reaction process is similar to that of Example 1. The concentration of 2-cyano-4-pyridine acid methyl ester solution is 0.7 mol / L. After the three-step reaction, MNI-137 yellow solid is obtained by recrystallization. The weighed yield is 85%. The purity is greater than 90% under HPLC monitoring.

[0061] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for the full-continuous synthesis of MNI-137, characterized in that: The following steps are involved: The organic metal reagent solution is mixed with the ethyl acetate solution, and reacted in a first microchannel reactor to obtain an enol intermediate; The enol intermediate is mixed with 2-cyano-4-pyridine acid methyl ester solution, reacted in a second microchannel reactor, quenched with acid, and separated to obtain an organic phase; The organic phase is mixed with a 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution, and reacted in a third microchannel reactor to obtain an intermediate. The intermediate is mixed with a trifluoroacetic acid solution, and reacted in a fourth microchannel reactor to obtain MNI-137; The organometallic reagent is selected from at least one of methyl lithium, n-butyl lithium, sec-butyl lithium, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide and potassium tert-butoxide.

2. The method according to claim 1, characterized in that The solvent in the organic metal reagent solution is selected from at least one of tetrahydrofuran, n-hexane, cyclohexane and n-heptane; The solvent in the ethyl acetate solution, 2-cyano-4-pyridine acid methyl ester solution, 1-Boc protected amino-2-amino-4-bromobenzene / triethylamine solution and trifluoroacetic acid solution is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, n-hexane, cyclohexane and n-heptane.

3. The method according to claim 1, characterized in that The acid is selected from at least one of dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid, citric acid, sodium citrate-citric acid buffer solution, acetic acid, trifluoroacetic acid, and ammonium chloride-dilute hydrochloric acid solution; The concentration of the acid is 0.5 to 3 mol / L; The acid contains at least one of sodium sulfate, sodium carbonate, sodium chloride, sodium hydrogen phosphate and sodium bicarbonate.

4. The method according to claim 1, characterized in that The molar ratio of the organic metal reagent solution to ethyl acetate is 2 to 2.6:1; The temperature of the reaction I is -20 to 20°C; The reaction time is 1 second to 3 minutes.

5. The method according to claim 1, characterized in that The molar ratio of 2-cyano-4-pyridinic acid methyl ester to ethyl acetate is 1:1-2; The temperature of the reaction II is -20 to 20°C; The reaction time of the reaction II is 1s to 3min; The quenching temperature is 0-20°C.

6. The method according to claim 1, characterized in that The molar ratio of the 1-Boc protected amino-2-amino-4-bromobenzene to triethylamine is 1:1 to 1.6; The molar ratio of the organic phase to 1-Boc protected amino-2-amino-4-bromobenzene is 1:1 to 1.6; The temperature of the reaction III is 0 to 40°C; The time of the reaction III is 5 to 10 minutes.

7. The method according to claim 1, characterized in that The molar ratio of the intermediate to trifluoroacetic acid is 1:10-20; The temperature of the reaction IV is 0 to 40°C; The time of the reaction IV is 15 to 30 minutes.

8. The method according to claim 1, characterized in that: The first microchannel reactor, the second microchannel reactor, the third microchannel reactor, and the fourth microchannel reactor are connected in sequence; The hydraulic diameters of the first microchannel reactor, the second microchannel reactor, the third microchannel reactor and the fourth microchannel reactor are 100 μm to 10 mm.

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