Process for the continuous production of alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate

Abstract

The present invention relates to a novel continuous process for preparing alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridinecarboxylates.

Description

Technical Field

[0001] The present invention relates to a novel process on an industrial scale for preparing alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 5 using continuous flow reaction conditions. Alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate 5 is a key intermediate for preparing the compounds described in WO2018 / 024653, WO2019 / 149657, WO2019 / 149658 and WO2019 / 149659.

Background Art

[0002] The synthesis of 4-amino-1,2,5-oxadiazole-3-carbonitrile 4 via intermediates 6 and 7 is described in T. Ichikawa et al. (J. Heterocycl. Chem. 1965, 253). Scheme 1

[0003]

Chemical Formula

[0004] The main drawback of the literature synthesis of 4-amino-1,2,5-oxadiazole-3-carbonitrile 4 is that the intermediate compounds 6 and 7 (like compound 4) are high-energy substances. D.S. Bohle et al. describe that compound 6 "explodes at about 130 °C during DSC experiments and shatters the sample cup" (J. Org. Chem 2000, 65, 1139). Furthermore, in order to induce the cyclization of compound 6 to oxadiazole 7, it is necessary to heat the aqueous reaction mixture under reflux. This can cause safety problems, especially when scaling up this conversion. Another important drawback of the synthesis according to the literature is the use of lead compounds for the deoximation of oxadiazole 7 to oxadiazole 4. The use of toxic lead in the preparation of pharmaceuticals is, in any case, questionable. However, in most of the literature descriptions, lead is used in stoichiometric or even higher amounts. Therefore, the weight load of the lead compound on the substrate is large. As a result, a large amount of toxic lead waste is generated. As another alternative to lead-containing reagents, WO2018 / 44663 describes the use of manganese(IV) oxide as a mild oxidant. However, since a significant amount of amide is formed as a by-product, the crude product was purified by column chromatography. This is a severe drawback on a technical scale, and on a large scale, column chromatography is very time-consuming and expensive. Furthermore, the risk of high-energy intermediates cannot be overcome by this method.

[0005] A.B. Sheremetev and V.A. Dorokhov et al. showed that ethyl acetoacetate adds to the nitrile group of 4-amino-1,2,5-oxadiazole-3-carbonitrile 4 in the presence of a catalytic amount of nickel(II) acetylacetonate in methylene chloride. When acetic acid is added and heated, ethyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate 5a is obtained via intramolecular cyclization (Mendeleev Communication 1994, 4, 57; Russian Chemical Bulletin, Int. Ed., 2001, 50, 1280). SUMMARY OF THE INVENTION

[0006] The present invention combines an integrated continuous flow system under overpressure with a batch reactor to obtain alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridinecarboxylate 5

[0007]

Chemical Formula

[0008]

Chemical formula

[0009]

Chemical formula

[0010]

Chemical formula

[0011] ; (e) removing water from the reaction mixture by phase separation; (f) compound 4 in the reaction mixture obtained after step (e) in a batch reactor in a suitable solvent in the presence of a Lewis acid such as zinc acetate, of the formula

[0012]

Chemical formula

[0013]

Chemical formula

[0014] The flow process according to the invention overcomes the disadvantages of the prior art methods by having the following characteristics. 1) Avoid high-energy intermediates 6 and 7. 2) Utilize inexpensive and readily available starting materials and reagents. 3) Avoid isolation of any intermediate so that only the final product needs to be isolated. 4) Eliminate the accumulation of all intermediates except 4. 5) Avoid distillation of the solution containing the high-energy intermediate 4. 6) Obtain alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 5 in high purity with a high average yield for each step. 7) Reduce the solvent required in all five steps by about 60% compared to a similar batch process.

[0015] Step (a) Suitable acids for step (a) include hydrohalic acids such as hydrochloric acid and hydrobromic acid, or organic acids such as acetic acid. Preferably, acetic acid is used. The solvent suitable for step (a) is water. Step (a) is preferably carried out at a temperature of 20 to 40 °C for 15 seconds to 5 minutes, preferably at a temperature of about 30 °C. The entire continuous flow process is preferably carried out in a system under an overpressure of at least 2 bar. The overpressure is caused by gas generation due to the chemical reaction in step (a) and overheating of the solvent in step (d), and is maintained by a back pressure regulator near the end of the reactor. Preferably, the overpressure is between 2 and 15 bar, more preferably between 6 and 10 bar.

[0016] Step (b) Examples of toluenesulfonic acid derivatives useful as the reagent in step (b) include p-toluenesulfonic anhydride and p-toluenesulfonyl chloride. Preferably, p-toluenesulfonyl chloride is used. Solvents suitable for step (b) include ether solvents such as 2-methyl-tetrahydrofuran (2-MeTHF) and 1,4-dioxane, water, and mixtures thereof. Step (b) is preferably carried out at a temperature of 20 to 40 °C for 15 seconds to 5 minutes, more preferably at a temperature of about 30 °C.

[0017] Step (c) Solvents suitable for step (c) include ethers such as 2-methyl-tetrahydrofuran (2-MeTHF) and 1,4-dioxane, water, and mixtures thereof. Step (c) is preferably carried out at a temperature of 20 to 40 °C for 15 seconds to 5 minutes, more preferably at a temperature of about 30 °C. Suitable hydroxylamine salts include ammonium hydroxyl chloride and ammonium hydroxyl sulfate. Ammonium hydroxyl chloride is preferred. Suitable bases for step (c) include organic bases such as triethylamine, or inorganic bases such as alkali acetates, alkali carbonates, and alkali hydrogen carbonates. Examples of suitable acetates are lithium acetate, sodium acetate, and potassium acetate. Examples of suitable carbonates are sodium carbonate and potassium carbonate. Examples of suitable hydrogen carbonates are sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably, potassium acetate is used.

[0018] Step (d) Suitable bases for step (d) include organic bases such as triethylamine, or inorganic bases such as alkali acetates, alkali carbonates, and alkali hydrogen carbonates. Examples of suitable acetates are lithium acetate, sodium acetate, and potassium acetate. Examples of suitable carbonates are sodium carbonate and potassium carbonate. Examples of suitable hydrogen carbonates are sodium hydrogen carbonate and potassium hydrogen carbonate. Preferably, potassium acetate is used. Suitable solvents for step (d) include ethers such as 1,4-dioxane and 2-methyl-tetrahydrofuran (2-MeTHF), water, and mixtures thereof. Step (d) is preferably carried out at a temperature of 110 to 130 °C, more preferably about 120 °C, for 15 seconds to 5 minutes under a pressure of at least 2 bar.

[0019] Step (e) Step (e) can be carried out continuously or batchwise, preferably at about 20 - 45 °C, using a non-polar solvent as the extraction solvent by means of a centrifugal extractor or a batch reactor. Heptane, isopropyl acetate, methyl tert-butyl ether and toluene are suitable non-polar extraction solvents. For continuous extraction, it is preferred to use toluene or methyl tert-butyl ether as the solvent. Most preferably for continuous extraction is to use methyl tert-butyl ether as the solvent at a temperature of about 30 °C. For batch extraction, methyl tert-butyl ether is preferred.

[0020] Step (f) Suitable beta-ketoesters for step (f) are selected from the group consisting of C 1-3 -alkyl beta-ketoesters. Preferably, ethyl beta-ketoester is used. Suitable Lewis acids for step (f) include zinc salts such as zinc acetate. Both zinc acetate dihydrate and anhydrous zinc acetate can be used. Preferably, zinc acetate dihydrate is used as the Lewis acid. Suitable solvents for step (f) include ethers such as 1,4-dioxane, 2-methyl-tetrahydrofuran (2-MeTHF) and methyl tert-butyl ether, alcohols such as ethanol, non-polar solvents such as toluene, and any mixtures thereof. The preferred ether is 1,4-dioxane and the preferred alcohol is ethanol. Step (f) is preferably carried out at a temperature of 60 - 100 °C, more preferably about 70 °C, for 2 - 24 hours. Step (g) In step (g), compound 5 is preferably isolated by distillation to remove toluene and 2-methyl-tetrahydrofuran (2-MeTHF), precipitated by the addition of an anti-solvent such as water, and isolated by filtration. Alternatively, by reacting the MTBE extract of 4 to obtain 5, either crystallization and isolation of 5 by simple addition of anti-solvent water or distillation of additional solvent during the reaction time to 5 can be carried out, and the space-time yield of the total yield can be increased. Apparatus Suitable flow reactors for steps (a) to (d) should be equipped with design features (such as collision points or static mixers, etc.) that promote mixing, especially for steps (b) and (c), be corrosion-resistant (e.g., glass or Hastelloy), be safely resistant to an operating pressure of up to 15 bar, be equipped with a back-pressure regulator to minimize or prevent boiling of the solvent, be capable of rapid heating and cooling (about 50 W / kg / h = 180 kJ / g to maintain selectivity), and have a residence time long enough for the reaction to occur and be completed. Additional safety features (such as safety valves, backflow prevention valves) are not essential. For pumps, it is necessary to select pumps with the required flow rate and pressure, preferably without pulsation or at least with less pulsation.

Brief Description of the Drawings

[0021]

Figure 1

Modes for Carrying Out the Invention

[0022] General Definitions Terms not explicitly defined in this specification should be given the meaning that would be indicated by those skilled in the art considering the present disclosure and context. When the compounds of the present invention are represented by chemical names and formulas, the formula shall take precedence in case of contradiction. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name encompasses tautomers, rotamers, and all stereoisomeric, optical, and geometric isomers (e.g., enantiomers, diastereomers including E / Z isomers, etc.) and racemates thereof, as well as mixtures of various proportions of the individual enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms in which their isomers and enantiomers are present, and their solvates such as hydrates, for example. Abbreviations s seconds min minutes A% area ratio Experimental Section Note: All intermediates are high-energy compounds and toxic gases are generated as by-products. Special attention is required for safety measures.

[0023] (Example 1) Synthesis of ethyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 5 by continuous extraction. (Steps a - g of the whole synthesis)

[0024]

Chemical Structure

[0025] 1. A solution of malononitrile (1.00 kg) in water (7.22 kg) and acetic acid (0.955 kg) was prepared in a stainless-steel mixing tank. The suspension was stirred until all solids dissolved. The resulting solution was passed through a charcoal cartridge and collected in a glass bottle to obtain a colorless transparent solution. (Stream 1) 2. Sodium nitrite (1.097 kg) and water (4.005 kg) were added to a glass bottle and stirred until the solids dissolved. (Stream 2) 3. Toluene sulfonyl chloride (3.088 kg) was added to a carboy and blanketed with nitrogen gas. 1,4-Dioxane (18.22 kg) and 2-methyltetrahydrofuran (6.290 kg) were added, and the suspension was stirred to dissolve the solid. (Stream 3) 4. Potassium acetate (5.067 kg), water (25.75 kg), hydroxylammonium chloride (1.073 kg), and 1,4-dioxane (12.93 kg) were added to a glass carboy. The suspension was stirred until all solids were dissolved. (Stream 4) 5. Each feed stream was connected to a pump suitable for delivering it.

[0026] 6. Pumps for Stream 1 (18.8 mL / min), Stream 2 (9.59 mL / min), Stream 3 (57 mL / min), Stream 4 (47 mL / min), and toluene (20 mL / min), and motors for the first centrifugation and the second centrifugation were started. The average residence times were 1.75 minutes, 1.75 minutes, 0.38 minutes, and 1.89 minutes in steps a, b, c, and d, respectively. The power supply for the heat exchange function was turned on. 7. The reaction mixture was discarded until the flow was equilibrated and the completion of all chemical conversions was observed as determined by HPLC, at which point the receiving vessel was replaced and the reaction mixture was collected. Typical conversions under these exact conditions are an HPLC A% greater than 97 at 210 nm (A%4 vs A%2 + A%3). 8. The aqueous and organic layers were collected until either of the starting material solutions was consumed or the desired run time was achieved. Each collection vessel was measured by HPLC to confirm that the process was operating properly (typical aqueous concentration = 0.1 - 0.2 mass% of oxadiazole 4, typical organic concentration = 2.2 - 2.4 mass%). 9. Zinc diacetate dihydrate (3.230 kg) was charged to an inert batch reactor. The organic layer was charged and the suspension was stirred.

[0027] 10. Ethyl acetoacetate (4.788 kg) was added to the batch reactor. 11. This batch was heated to 70 °C and left for 24 hours. 12. After the target conversion rate was achieved, the suspension was distilled and 1,4-dioxane was added until 2-MeTHF and toluene were removed. 13. Water was added and the temperature inside the batch was maintained at 65 - 70 °C. 14. After crystallization occurred, the batch was aged at 65 - 70 °C for 20 minutes. 15. The batch was cooled to room temperature over approximately 1 hour. 16. The batch was filtered. 17. The cake was washed with water (4.000 kg). 18. The cake was transferred to a tray and dried at 40 °C for 16 hours under a nitrogen gas purge to obtain a solid (total yield 35%, 1.170 kg).

[0028] 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.61 (bs, 2H), 4.35 (q, 2H), 2.62 (s, 3H), 1.34 (t, 3H). HPLC area % at 210 nm > 98%. Another aspect of the present invention may be as follows. 〔1〕By combining an integrated continuous flow system under overpressure with a batch reactor, alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 5

Chemical Structure

Chemical Structure

Chemical Structure

Chem.

Chem.

Claims

1. A method for producing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate 5 by combining an integrated continuous flow system under overpressure with a batch reactor, comprising: 【Chemical 1】 5 (wherein R is C 1-3 -alkyl) (a) reacting malononitrile with sodium nitrite in the presence of a suitable acid in a suitable solvent; (b) reacting the reaction mixture obtained in step (a) with a suitable toluenesulfonic acid derivative to obtain compound 2; (c) reacting compound 2 with hydroxylamine or a suitable hydroxylamine salt in a suitable solvent to obtain compound 3; 【Chemical 2】 2 (d) cyclizing compound 3 by heating to about 120° C. in the presence of a base in a suitable solvent to obtain oxadiazole 4; (e) removing water from the reaction mixture by phase separation; [Chemical 3] 3 (f) condensing compound 4 in the reaction mixture obtained after step (e) in situ with a suitable β-ketoester of the formula in a suitable solvent in the presence of a Lewis acid in a batch reactor; and 【Chemical 4】 4 (g) isolating compound 5 from the batch reactor. A method comprising the steps of:

2. 【Chemical Formula 5】 (wherein R is C 1-3 -alkyl) The method according to claim 1, wherein in step (a), hydrochloric acid, hydrobromic acid or acetic acid is used as the suitable acid, and water is used as the solvent.

3. The method according to claim 1 or 2, wherein step (a) is carried out at a temperature of 20 to 40° C. for 15 seconds to 5 minutes under an overpressure of at least 2 bar.

4. The method according to any one of claims 1 to 3, wherein in step (a), acetic acid is used as the suitable acid and water is used as the solvent at a temperature of about 30° C. for 15 seconds to 5 minutes.

5. The method according to any one of claims 1 to 4, wherein in step (b), the toluenesulfonic acid derivative is toluenesulfonic anhydride or toluenesulfonyl chloride, and the reaction is carried out at a temperature of 20 to 40° C. for 15 seconds to 5 minutes.

6. The method according to any one of claims 1 to 5, wherein in step (b), the toluenesulfonic acid derivative is toluenesulfonyl chloride, and the reaction is carried out at a temperature of about 30° C. for 15 seconds to 5 minutes.

7. ​ ​ ​ ​ The method according to any one of claims 1 to 6, wherein in step (c), ether, water or a mixture thereof is used as the solvent, and the reaction is carried out at a temperature of 20 to 40 ° C for 15 seconds to 5 minutes.

8. The method according to any one of claims 1 to 7, wherein in step (c), 2-methyl-tetrahydrofuran, 1,4-dioxane, water, or a mixture thereof is used as the suitable solvent, and hydroxylamine hydrochloride ammonium is used as the suitable hydroxylamine salt, and the reaction is carried out at a temperature of about 30 ° C for 15 seconds to 5 minutes.

9. The method according to any one of claims 1 to 8, wherein in step (d), the cyclization is carried out at a temperature of 110 to 130 ° C for 15 seconds to 5 minutes under a pressure of at least 2 bar in the presence of ether, water or a mixture thereof as the solvent and in the presence of triethylamine, an alkali acetate, an alkali carbonate or an alkali bicarbonate.

10. The method according to claim 9, wherein in step (d), the alkali acetate is selected from the group consisting of lithium acetate, sodium acetate, and potassium acetate; the alkali carbonate is selected from the group consisting of sodium carbonate and potassium carbonate; the alkali bicarbonate is selected from the group consisting of sodium bicarbonate and potassium bicarbonate; and the ether is 1,4-dioxane or 2-methyltetrahydrofuran.

11. The method according to any one of claims 1 to 10, wherein in step (e), water is removed by extraction at about 20 to 45 ° C using a non-polar extraction solvent selected from the group consisting of toluene, methyl tert-butyl ether, heptane, and isopropyl acetate.

12. The method according to any one of claims 1 to 11, wherein in step (e), water is continuously removed by extraction at about 20 to 45 ° C using toluene or methyl tert-butyl ether as the extraction solvent.

13. The method according to any one of claims 1 to 12, wherein in step (e), water is continuously removed by extraction at about 30 ° C using methyl tert-butyl ether as the extraction solvent.

14. The method according to any one of claims 1 to 13, characterized in that in step (e), water is removed in a batch process at about 20 °C using methyl tert-butyl ether as the extraction solvent.

15. The method according to any one of claims 1 to 14, characterized in that in step (f), the in-situ condensation is carried out at a temperature of 60 to 100 °C for 2 to 24 hours in a solvent selected from the group consisting of ethers, alcohols, non-polar solvents, or mixtures thereof, in the presence of a zinc salt as a Lewis acid.

16. The method according to any one of claims 1 to 15, characterized in that in step (f), the in-situ condensation is carried out at a temperature of 60 to 100 °C for 2 to 24 hours in a solvent selected from the group consisting of 1,4-dioxane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, and ethanol, and mixtures thereof, in the presence of zinc acetate as the Lewis acid.

17. The method according to any one of claims 1 to 16, characterized in that in step (g), compound 5 is precipitated by the addition of an anti-solvent and then isolated by filtration, the anti-solvent being water.

18. The method according to claim 17, characterized in that before precipitating compound 5 in step (g), the reaction solvent is distilled off.

19. The method according to any one of claims 1 to 18, wherein R is ethyl.

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