Continuous process for preparing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to an industrial-scale method for manufacturing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylates using continuous flow reaction conditions. 5 The alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylates 5 are key intermediates for manufacturing the compounds described in WO 2018 / 024653, WO 2019 / 149657, WO 2019 / 149658 and WO 2019 / 149659. BACKGROUND ART

[0002] 4-Amino-1,2,5-oxadiazole-3-carbonitrile 4 is elaborated via intermediates 6 and 7 by T. Ichikawa et al. (J. Heterocycl. Chem. 1965, 253).

[0003] SCHEME 1

[0004]

[0005] In 2017, P. F. Pagoria et al. published a modification of the Ichikawa route with improved yield and purity (Chem. Heterocycl. Compounds 2017, 53, 760).

[0006] 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 (and compound 4 ) are high-energy substances. D. S. Bohle et al. elaborated that compound 6 "exploded during a DSC test at about 130 °C, shattering the sample cup" (J. Org. Chem 2000, 65, 1139). In addition, to effect the cyclization of compound 6 to oxadiazole 7 the aqueous reaction mixture must be heated under reflux. This can pose safety problems, especially in the scale-up of this transformation.

[0007] Another important drawback of the literature synthesis is the use of lead compounds for the conversion of oxadiazole 7 to oxadiazole 4The deoximation group. In any case, the use of toxic lead during drug manufacturing is problematic. However, in most literature descriptions, lead is even used in stoichiometric amounts or higher. Therefore, the weight load of lead compounds relative to the substrate is high. As a result, a large amount of toxic lead waste is generated.

[0008] As an alternative to lead-containing reagents, WO 2018 / 44663 describes the use of manganese(IV) oxide as a mild oxidant. However, due to the formation of a large amount of amide as a by-product, the crude product is purified by column chromatography. This is a serious drawback for industrial scale because, on a large scale, column chromatography is extremely time-consuming and expensive. In addition, this method fails to overcome the risk of high-energy intermediates.

[0009] 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 in dichloromethane in the presence of a catalytic amount of nickel(II) acetylacetonate 4 By adding acetic acid and heating, ethyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate is obtained via intramolecular cyclization 5 a (Mendeleev Communication 1994, 4, 57; Russian Chemical Bulletin, Int. Ed., 2001, 50, 1280). Detailed Description

[0010] The present invention provides a method for preparing a compound 5 of

[0011]

[0012] wherein R in the compound 5 is C 1-3 -alkyl,

[0013] Implemented by combining an integrated continuous flow system under superpressure with a batch reactor, the method comprises the following steps:

[0014] (a) Reacting malononitrile with sodium nitrite in the presence of a suitable acid, preferably in the presence of acetic acid;

[0015] (b) Reacting the reaction mixture obtained by step (a) with a suitable toluenesulfonic acid derivative, preferably p-toluenesulfonyl chloride, to obtain a compound 2 ;

[0016]

[0017] (c) Reacting the compound 2React with hydroxylamine or a suitable hydroxylamine salt to obtain a compound 3 ;

[0018]

[0019] (d) Cyclize the compound 3 by heating to about 120 °C in the presence of a base to obtain a compound 4 ;

[0020]

[0021] (e) Remove water from the reaction mixture by phase separation;

[0022] (f) In a batch reactor, in the presence of a Lewis acid (e.g., zinc acetate), condense the compound 4 in the reaction mixture obtained after step (e) in situ with a suitable β-ketoester of the formula 6 wherein R in the formula

[0023]

[0024] is C 6 -alkyl, 1-3 -alkyl,

[0025] and

[0026] (g) Separate the compound 5 .

[0027] In the above process, the β-ketoester is a C 1-3 -alkyl β-ketoester. Preferably, ethyl β-ketoester is used. Accordingly, in Scheme 2 below, R is C 1-3 -alkyl. Preferably, R is ethyl.

[0028] The process of the present invention is suitable for use on an industrial scale.

[0029] Scheme 2 (n.i. = not isolated)

[0030]

[0031] The flow process of the present invention overcomes the disadvantages of the prior art processes by having the following characteristics

[0032] 1) Avoid high-energy intermediates 6 and 7 ,

[0033] 2) Utilize inexpensive and readily available starting materials and reagents,

[0034] 3) Avoid separating any intermediates such that only the final product needs to be separated.

[0035] 4) Eliminate the accumulation of all intermediates except 4

[0036] 5) Avoid distilling solutions containing high-energy intermediates 4

[0037] 6) Obtain alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate 5

[0038] 7) Reduce the total solvent required for all five steps by about 60% compared to a similar batch method.

[0039] Step (a)

[0040] 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.

[0041] A suitable solvent for step (a) is water.

[0042] Step (a) is preferably carried out at a temperature of 20 to 40 °C, preferably at a temperature of about 30 °C for 15 s to 5 min.

[0043] The entire continuous flow method is preferably carried out in a system having a superpressure of at least 2 bar. The superpressure is caused by the gas evolution from the chemical reaction in step (a) and by the overheating of the solvent in step (d) and is maintained by a backpressure regulator near the end of the reactor. Preferably, the superpressure is between 2 and 15 bar, more preferably between 6 and 10 bar.

[0044] Step (b)

[0045] Suitable toluenesulfonic acid derivatives that can be usefully employed as reagents for step (b) include p-toluenesulfonic anhydride and p-toluenesulfonyl chloride. Preferably, p-toluenesulfonyl chloride is used.

[0046] Suitable solvents for step (b) include ether solvents (such as 2-methyl-tetrahydrofuran (2-MeTHF) and 1,4-dioxane), water, and mixtures thereof.

[0047] Step (b) is preferably carried out at a temperature of 20 to 40 °C, more preferably at a temperature of about 30 °C for 15 s to 5 min.

[0048] Step (c)

[0049] ​​​Suitable solvents for step (c) include ethers (e.g., 2-methyl-tetrahydrofuran (2-MeTHF) and 1,4-dioxane), water, and mixtures thereof.

[0050] Step (c) is preferably carried out at a temperature of 20 to 40 °C, more preferably at a temperature of about 30 °C, for 15 s to 5 min.

[0051] Suitable hydroxylamine salts include hydroxylammonium chloride and hydroxylammonium sulfate. Hydroxylammonium chloride is preferred. Suitable bases for step (c) include organic bases (e.g., triethylamine) or inorganic bases such as alkali metal acetates, alkali metal carbonates, and alkali metal bicarbonates. 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 bicarbonates are sodium bicarbonate and potassium bicarbonate. Preferably, potassium acetate is used.

[0052] Step (d)

[0053] Suitable bases for step (d) include organic bases (e.g., triethylamine) or inorganic bases such as alkali metal acetates, alkali metal carbonates, and alkali metal bicarbonates. 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 bicarbonates are sodium bicarbonate and potassium bicarbonate. Preferably, potassium acetate is used.

[0054] Suitable solvents for step (d) include ethers (e.g., 1,4-dioxane and 2-methyl-tetrahydrofuran (2-MeTHF)), water, and mixtures thereof.

[0055] Step (d) is preferably carried out at a temperature of 110 to 130 °C, more preferably at a temperature of about 120 °C and at a pressure of at least 2 bar, for 15 s to 5 min.

[0056] Step (e)

[0057] Step (e) can be carried out continuously or batchwise, preferably at about 20 to 45 °C, using a centrifugal extractor or a batch reactor and using a non-polar solvent as the extraction solvent. Heptane, isopropyl acetate, methyl tert-butyl ether, and toluene are suitable non-polar extraction solvents. Using toluene or methyl tert-butyl ether as the solvent is preferred for continuous extraction. The best for continuous extraction is to use methyl tert-butyl ether as the solvent at a temperature of about 30 °C. Methyl tert-butyl ether is preferably used for batch extraction.

[0058] Step (f)

[0059] Suitable β-keto esters for step (f) are selected from the group consisting of C 1-3 -alkyl β-keto esters. Preferably, ethyl β-keto ester is used.

[0060] 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.

[0061] 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. Preferably, the ether is 1,4-dioxane and the alcohol is ethanol.

[0062] Step (f) is preferably carried out at a temperature of 60 to 100 °C, more preferably at a temperature of about 70 °C, for 2 - 24 h.

[0063] Step (g)

[0064] In step (g), the compound 5 is preferably separated by distillation to remove toluene and 2-methyl-tetrahydrofuran (2-MeTHF), precipitated by the addition of an anti-solvent (such as water), and separated by filtration.

[0065] Alternatively, 4 the MTBE extract of 5 is reacted in ethanol to produce 5 allowing crystallization and separation by simply adding the anti-solvent water or by distilling off additional solvent during the reaction time towards 5 which increases the space-time yield of the overall yield.

[0066] Equipment

[0067] Suitable flow reactors for steps (a) - (d) contain design features (such as impingement points or static mixers) to facilitate mixing, especially for steps (b) and (c), are corrosion-resistant (such as glass or Hastelloy), can safely withstand operating pressures up to 15 bar, have a back-pressure regulator to minimize or prevent solvent boiling, can be rapidly heated and cooled (about 50 W / kg / h = 180 kJ / g to maintain selectivity), and have a long enough residence volume for the reaction to occur to completion. Additional safety features (such as safety valves, check valves) are optional. The pump should be selected based on its ability to pump at the required flow rate and pressure, preferably being pulsation-free, at least having low pulsation.

[0068] Figure 1 Schematic diagram of the overall reactor showing the method of the present invention.

[0069] General definitions

[0070] Terms not explicitly defined herein should be given the meaning that would be given by a person skilled in the art based on the disclosure and context.

[0071] If the compounds of the present invention are described in chemical name form or as chemical formulas, in case of ambiguity, the chemical formula shall prevail.

[0072] Unless otherwise specified, throughout the specification and the appended claims, a given chemical formula or name shall cover tautomers, rotamers, and all stereoisomers, optical isomers, and geometric isomers (such as enantiomers, diastereomers, including E / Z isomers, etc.), as well as their racemates and mixtures of individual enantiomers, diastereomers, or any of the above forms in the presence of said isomers and enantiomers in different proportions, and their solvates (such as hydrates).

[0073] Abbreviations

[0074] s second

[0075] min minute

[0076] A% area percentage

[0077] Experimental section

[0078] Note: All intermediates are high-energy compounds and produce toxic gases as by-products. Special attention must be paid to safety measures.

[0079] Example 1

[0080] Ethyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate 5 Synthesis using continuous extraction

[0081] (Steps a-g of the overall synthesis)

[0082]

[0083] 1. Prepare a solution of malononitrile (1.00 kg) in water (7.22 kg) and acetic acid (0.955 kg) in a stainless-steel mixing tank. Stir the suspension until all solids are dissolved. Pass the resulting solution through a carbon cartridge and collect it in a glass bottle to provide a clear, colorless solution. (Stream 1)

[0084] 2. Add sodium nitrite (1.097 kg) and water (4.005 kg) to the glass bottle and stir until the solids are dissolved. (Stream 2)

[0085] 3. Add tosyl chloride (3.088 kg) to a flask and cover it with a nitrogen blanket. Add 1,4-dioxane (18.22 kg) and 2-methyltetrahydrofuran (6.290 kg) and stir the suspension to dissolve the solids. (Stream 3)

[0086] 4. Add potassium acetate (5.067 kg), water (25.75 kg), hydroxylammonium chloride (1.073 kg) and 1,4-dioxane (12.93 kg) to a glass jar. Stir the suspension until all solids are dissolved. (Stream 4)

[0087] 5. Connect each feed stream to a pump suitable for pumping it.

[0088] 6. Start the pumps for Streams 1 (18.8 mL / min), 2 (9.59 mL / min), 3 (57 mL / min), 4 (47 mL / min) and toluene (20 mL / min) and the motors for the first and second centrifuges. The average residence times for steps a, b, c and d are 1.75 min, 1.75 min, 0.38 min and 1.89 min respectively. The heat exchange function has been started.

[0089] 7. Discard the reaction mixture until flow equilibrium is achieved and all chemical conversions are observed to be complete, as determined by HPLC, at which point change the receiving vessel and collect the reaction mixture. The typical conversion under these exact conditions is >97 HPLC A% (A% 4 vs A% 2 + A% 3) at 210 nm.

[0090] 8. Collect the aqueous and organic layers until either starting material solution is exhausted or until the desired run time is reached. Analyze each collection vessel by HPLC to ensure normal process operation (typical aqueous layer concentration = 0.1 - 0.2 wt% oxadiazole 4 , typical organic layer concentration = 2.2 - 2.4 wt%).

[0091] 9. Load zinc acetate dihydrate (3.230 kg) into an inerted batch reactor. Load the organic layer and agitate the suspension.

[0092] 10. Add ethyl acetoacetate (4.788 kg) to the batch reactor.

[0093] 11. Heat the batch to 70 °C for 24 h.

[0094] 12. Once the target conversion is achieved, distill the suspension and add 1,4-dioxane until 2-MeTHF and toluene are removed.

[0095] 13. Add water to maintain the internal batch temperature between 65 °C and 70 °C.

[0096] 14. After crystallization occurs, age the batch at 65–70 °C for 20 minutes.

[0097] 15. Cool the batch to room temperature over approximately 1 h.

[0098] 16. Filter the batch material.

[0099] 17. Wash the filter cake with water (4.000 kg).

[0100] 18. Transfer the filter cake to a tray and dry it under a nitrogen purge at 40 °C for 16 h to obtain the solid (35% overall yield, 1.170 kg).

[0101] 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.61 (bs, 2H), 4.35 (q, 2H), 2.62 (s, 3H), 1.34 (t, 3H).

[0102] HPLC area % at 210 nm > 98%.

Claims

1. A method for preparing a compound 5 is provided. Among them, the compound 5 wherein R is C 1-3 -alkyl The method is implemented by combining an integrated continuous flow system under superpressure with a batch reactor, and the method comprises the following steps: (a) Reacting malononitrile with sodium nitrite in a suitable solvent in the presence of a suitable acid; (b) React the reaction mixture obtained in step (a) with a suitable toluenesulfonic acid derivative to obtain the compound 2 ; (c) React the compound 2 with hydroxylamine or a suitable hydroxylamine salt in a suitable solvent to obtain the compound 3 ; (d) Heat the compound in a suitable solvent in the presence of a base to about 120 °C to effect cyclization to obtain the compound 3 ; 4 ; (e) Removing water from the reaction mixture obtained in step (d) by phase separation; (f) In a batch reactor, in the presence of a Lewis acid and in a suitable solvent, the compound in the reaction mixture obtained after step (e) 4 is condensed in situ with a suitable β-ketoester of the formula 6 ​ Wherein in the formula 6 R is C 1-3 -alkyl; and (g) Separating the compound from the batch reactor 5 .

2. 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 sec to 5 min under a superpressure of at least 2 bar (bar).

4. The method according to claim 1 or 2, 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 sec to 5 min.

5. The method according to claim 1 or 2, wherein in step (b), the toluenesulfonic acid derivative is toluenesulfonic anhydride or tosyl chloride, and the reaction is carried out at a temperature of 20 to 40 °C for 15 sec to 5 min.

6. The method according to claim 1 or 2, wherein in step (b), the toluenesulfonic acid derivative is tosyl chloride, and the reaction is carried out at a temperature of about 30 °C for 15 sec to 5 min.

7. The method according to claim 1 or 2, wherein in step (c), the reaction is carried out at a temperature of 20 to 40 °C using an ether, water or a mixture thereof as the solvent for 15 s to 5 min.

8. The method according to claim 1 or 2, wherein in step (c), the reaction is carried out at a temperature of about 30 °C, using 2-methyl-tetrahydrofuran, 1,4-dioxane, water or a mixture thereof as the suitable solvent and hydroxylammonium chloride as the suitable hydroxylamine salt for 15 s to 5 min.

9. The method according to claim 1 or 2, wherein in step (d), the cyclization is carried out in the presence of triethylamine, an alkali metal acetate, an alkali metal carbonate or an alkali metal bicarbonate using an ether, water or a mixture thereof as the suitable solvent at a temperature of 110 to 130 °C under a pressure of at least 2 bar for 15 s to 5 min.

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

11. The method according to claim 1 or 2, wherein in step (e), water is removed by extraction using a non-polar extraction solvent at 20 to 45 °C.

12. The method according to claim 1 or 2, wherein in step (e), water is removed by extraction using toluene, methyl tert-butyl ether, heptane or isopropyl acetate as the extraction solvent at 20 to 45 °C.

13. The method according to claim 1 or 2, wherein in step (e), water is continuously removed by extraction using toluene or methyl tert-butyl ether as an extraction solvent at 20 to 45 °C.

14. The method according to claim 1 or 2, wherein in step (e), water is continuously removed by extraction using methyl tert-butyl ether as an extraction solvent at about 30 °C.

15. The method according to claim 1 or 2, wherein in step (e), water is removed using methyl tert-butyl ether as an extraction solvent at about 20 °C in a batch process.

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

17. The method according to claim 1 or 2, wherein in step (f), the in-situ condensation is carried out in the presence of zinc acetate at a temperature of 60 to 100 °C in a solvent selected from 1,4-dioxane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, and ethanol and mixtures thereof for 2 to 24 hours.

18. The method according to claim 1 or 2, wherein in step (g), the compound 5 is precipitated by adding an anti-solvent and then separated by filtration.

19. The method according to claim 1 or 2, wherein in step (g), the compound 5 is precipitated by the addition of water and then separated by filtration.

20. The method according to claim 18, wherein the reaction solvent is distilled off before the precipitated compound 5 is precipitated.

21. The method according to claim 19, wherein the reaction solvent is distilled off before the precipitation compound 5 is precipitated.

22. The method according to claim 20 or 21, wherein the reaction solvent is distilled out during the course of the reaction itself.

23. The method according to claim 1 or 2, wherein R is ethyl.

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