Process for producing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate

Abstract

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

Description

Technical Field

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

Background Art

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

Chemical Formula

[0003] 4-amino-1,2,5-oxadiazole-3-carbonitrile 3 The main drawback of the literature synthesis of is that the intermediate compounds 6 and 7 (similar to compound 3 ) are high-energy substances. D.S. Bohle et al. describe that compound 6 "explodes at about 130 °C during DSC experiments and pulverizes the sample cup" (J. Org. Chem 2000, 65, 1139). Furthermore, the oxadiazole of compound 6 ​7 To induce cyclization, it is necessary to heat the aqueous reaction mixture under reflux. This can cause safety problems, especially when scaling up this conversion. Another significant drawback of the synthesis according to the literature is the use of lead compounds for the deoximation from oxadiazole 7 to oxadiazole 3 Using lead, which is toxic, 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 an 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.

[0004] 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 3 in methylene chloride in the presence of a catalytic amount of nickel(II) acetylacetonate. When acetic acid is added and heated, ethyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate 4a is obtained (Mendeleev Communication 1994, 4, 57; Russian Chemical Bulletin, Int. Ed., 2001, 50, 1280). SUMMARY OF THE INVENTION

[0005] The present invention relates to alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 4 [Chemical formula] 4 (wherein R is C 1-3 -alkyl) A method for producing (a) Reacting malononitrile with sodium nitrite under a slight overpressure in the presence of a suitable acid, preferably hydrobromic acid, in a suitable solvent; (b) Reacting the reaction mixture obtained in step (a) with a suitable toluenesulfonic acid derivative, preferably p-toluenesulfonyl chloride, to obtain the compound 1

[0006] [Chemical formula] 1 ; (c) Optionally, isolating the compound 1 ; (d) Reacting the compound 1 with hydroxylamine in a suitable solvent to obtain the compound 2 :

[0007] [Chemical formula] 2 ; (e) Optionally, isolating the compound 2 ; (f) Cyclizing the compound 2 by heating to about 70 °C in the presence of a base in a suitable solvent to obtain an oxadiazole 3

[0008] [Chemical formula] 3 A step of obtaining; (g) A step of removing water from the reaction mixture by evaporation under reduced pressure; (h) A step of removing the p-toluenesulfonate by filtration; (i) The compound in the reaction mixture obtained after step (h) 3 In a suitable solvent, in the presence of a Lewis acid such as zinc dichloride, of the formula

[0009]

Chemical formula

[0010] The method according to the present invention can be used on an industrial scale. Scheme 2 (n.i. = not isolated)

Chemical formula

[0011] The method according to the present invention overcomes the disadvantages of the prior art methods by having the following features. 1) Avoid high-energy intermediates 6 and 7 to avoid. 2) Utilize inexpensive and readily available starting materials and reagents. 3) Only two intermediates and the final product need to be isolated, and all of these can be easily carried out on an industrial scale. 4) Alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 4 can be obtained with high purity and high overall yield. Additional advantages of the method according to the present invention are as follows. i) Intermediate 2 to oxadiazole 3 The cyclization can be carried out under mild reaction conditions (for several hours at 70 °C) without the need for an oxidizing reagent. This can reduce the risk associated with high-energy compounds 3 ii) Intermediate 2 to oxadiazole 3 The use of the tosylate group as a good leaving group that promotes the intramolecular cyclization from iii) Intermediate 1 and 2 are highly crystalline compounds, so isolation and purification are easy. iv) There is no need to isolate the high-energy oxadiazole compound 3 formed in situ. After partially removing water and removing the p-toluenesulfonate, the reaction solution is further cyclo-condensed with a suitable beta-ketoester to obtain the bicyclic oxadiazole compound 4 with good overall yield and purity.

[0012] Examples of acids suitable for step (a) include hydrohalic acids such as hydrochloric acid and hydrobromic acid, or organic acids such as acetic acid. Preferably, hydrobromic acid is used. The solvent suitable for step (a) is water. Step (a) is preferably carried out at a temperature of 0 to 25 °C, preferably 2 to 20 °C, under a slight overpressure up to 0.3 bar. This overpressure is due to the reaction itself caused by the formation of nitrogen oxides and should be maintained to some extent to obtain a good yield. ​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. Examples of solvents suitable for step (b) include lipophilic solvents such as toluene, water, and mixtures thereof. Step (b) is preferably carried out at a temperature of 10 to 30 °C, more preferably at a temperature of about 20 °C.

[0013] In step (c), preferably, the compound is precipitated through the addition of an anti-solvent such as an alcohol such as 2-propanol 1 and isolated by filtration. Examples of solvents suitable for step (d) include ethers such as tetrahydrofuran, alcohols such as 2-propanol, water, and mixtures thereof. Step (d) is preferably carried out at a temperature of 10 to 30 °C, more preferably at a temperature of 20 to 25 °C. In step (e), preferably, the compound is precipitated through the addition of an anti-solvent such as water 2 and isolated by filtration.

[0014] Examples of bases suitable for step (f) include organic bases such as triethylamine, or inorganic bases such as alkali carbonates and alkali hydrogencarbonates. Examples of suitable carbonates are lithium carbonate, sodium carbonate, and potassium carbonate. Examples of suitable hydrogencarbonates are lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate. Preferably, potassium hydrogencarbonate is used because the resulting potassium p-toluenesulfonate has low solubility in the solvent used and can therefore be easily removed by filtration. Examples of solvents suitable for step (f) include ethers such as 1,4-dioxane, water, and mixtures thereof. Step (f) is preferably carried out at a temperature of 20 to 100 °C, more preferably at a temperature of 60 to 80 °C.

[0015] The beta-ketoesters suitable for step (i) are selected from the group consisting of C 1-3 -alkyl beta-ketoesters. Preferably, ethyl beta-ketoester is used. Examples of the Lewis acid suitable for step (i) include zinc salts such as zinc diacetate or zinc dichloride. Preferably, zinc dichloride is used as the Lewis acid. Examples of the solvent suitable for step (i) include ethers such as 1,4-dioxane (preferred when carrying out reaction step (i) in situ) or alcohols such as ethanol (preferred when carrying out the addition and separation step of the compound 3 ), or mixtures thereof. Step (i) is preferably carried out at a temperature of 20 to 100 °C, more preferably 60 to 80 °C. In step (i), the compound 4 is preferably precipitated by the addition of an anti-solvent such as water and isolated by filtration. Another aspect of the present invention may be as follows. 〔1〕Alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 4

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Mode for Carrying Out the Invention

[0016] General Definitions Terms not expressly defined in this specification should be given the meaning that would be ascribed by one of ordinary skill in the art, considering the present disclosure and the context. Where the compounds of the invention are represented by chemical names and formulas, the formula shall prevail in case of conflict. 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 such isomers and enantiomers are present, and their solvates such as hydrates, for example. Experimental Section Note: All intermediates are high-energy compounds. Special care is required for safety measures.

[0017] (Example 1) (Tosyloxy)carbonimidoyl dicyanide 1 Synthesis (Step 1 of the overall synthesis)

Chemical Structure

[0018] 38.3 kg (227.1 mol) of hydrobromic acid (48%) and subsequently 7.5 L of purified water (for washing) are added to a mixture of 7.5 kg (113.5 mol) of malononitrile in 38 L of purified water. At a temperature of 7 °C, a solution of 15.7 kg (227.1 mol) of sodium nitrite in 26.5 L of purified water is added over 2 hours. The feed tank is washed with 3.8 L of purified water, and the reaction mixture is stirred at 7 °C for 30 minutes (nitrous acid gas with a slight overpressure is generated). The temperature is raised to 20 °C over 1 hour, and the reaction mixture is stirred at 20 °C until the reaction to the intermediate is complete (monitored by TLC; the reaction is complete in about 30 minutes to 1 hour). The reaction mixture is added to a mixture of 22.7 kg (119.2 mol) of p-toluenesulfonyl chloride and 0.63 kg (2.25 mol) of tetra-n-butyl-ammonium chloride in 30 L of toluene. The feed tank is washed with 7.5 L of purified water. At a temperature of 20 °C, a solution of 9.55 kg (119.2 mol) of sodium hydroxide (50% in water) in 25 L of purified water is added over 45 minutes. The feed tank is washed with 3.5 L of purified water (the pH value should not exceed 4). The reaction mixture is stirred at 20 °C for 18 hours. After completion of the reaction (monitored by TLC), optionally 1 4 g of seed crystals (obtained from a small-scale experiment), and subsequently 30 L of 2-propanol are added. The mixture is stirred for 1 hour. The suspension is centrifuged, the filter cake is washed with 15 L of purified water, and then washed twice with 15 L of 2-propanol. The product is dried in a vacuum drying cabinet under inert conditions at 30 °C. Yield: 23.1 kg as a solid of 1 (82% of the theoretical value). 1 H NMR (400 MHz, CDCl3) δ (ppm) = 7.91 (d, 2H), 7.45 (d, 2H), 2.51 (s, 3H)

[0019] (Example 2) 2-Amino-2-(hydroxyimino)-N-(tosyloxy)acetimidoyl cyanide 2 Synthesis (Step 2 of the overall synthesis) [Chemical formula] Dissolve 23.49 kg (94.24 mol) of 1 in 17 L of tetrahydrofuran (stabilized) and 47 L of 2-propanol. To this solution, add a solution of 11.21 kg (127.28 mol) of hydroxylamine (37.6 w% in water) in 24 L of 2-propanol while keeping the temperature below 25 °C. Wash the feed tank with 17 L of 2-propanol. Stir the suspension at 20 °C for 2 hours. After completion of the reaction (monitored by HPLC), add 106 L of purified water over 30 minutes at 20 °C. Stir this suspension at 20 °C for 1 hour. Centrifuge the suspension and wash the filter cake twice with 35 L of 2-propanol. Dry the product in a vacuum drying cabinet at a temperature below 30 °C. Yield: 20.36 kg of 2 (76.5% of the theoretical value). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 11.7 (s, 1H), 8.05 (d, 2H), 7.53 (d, 2H), 6.13 (bs, 2H), 2.45 (s, 3H)

[0020] (Example 3) Ethyl 7-amino-5-methyl-[1,2,5]-oxadiazolo[3,4-b]pyridine carboxylate 4 Synthesis (Steps 3 + 4 of the overall synthesis) [Chemical formula]

[0021] 15.25 kg (54.02 mol) of 2A mixture of and 8.11 kg (81.0 mol) of potassium hydrogen carbonate is stirred at 70 °C. After completion of the reaction (monitored by HPLC; about 8 hours), 45.8 L of the solvent is evaporated under reduced pressure. 31 L of 1,4-dioxane is added and 61 L of the solvent is evaporated under reduced pressure (removing water). The suspension is cooled to 20 °C and filtered through an overpressure filter into a second reaction vessel containing a mixture of 7.37 kg (54.07 mol) of zinc dichloride in 15 L of 1,4-dioxane. The first reaction vessel is washed with 23 L of 1,4-dioxane and the solvent is filtered through the overpressure filter into the second reaction vessel. 7.03 kg (54.02 mol) of ethyl acetoacetate is added and the feed tank is washed with 8 L of 1,4-dioxane. The reaction mixture is stirred at 70 °C. After completion of the reaction (monitored by HPLC; the reaction is complete in about 20 hours), the reaction mixture is cooled to 50 °C and 122 L of purified water is added. The mixture is stirred at 50 °C for 30 minutes. The suspension is cooled to 20 °C and stirred for 30 minutes. The suspension is centrifuged and the filter cake is washed twice with 15 L of purified water. The product is dried in a vacuum drying cabinet under inerting at 40 °C. Yield: 7.71 kg as a solid of 4 (64.3% of theoretical). 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.60 (bs, 2H), 4.35 (q, 2H), 2.60 (s, 3H), 1.32 (t, 3H)

[0022] (Example 4) 4-Amino-1,2,5-oxadiazole-3-carbonitrile 3 (and 5-Amino-1,2,4-oxadiazole-3-carbonitrile as an unexpected by-product 5 ) synthesis (Step 3 of the overall synthesis)

Chemical formula

[0023] Purify the crude product by chromatography on silica gel using petroleum ether / ethyl acetate (3:1) as the eluent. Yield: 200 mg of 3 (51% of theory). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.09 (bs, 2H) 13 C NMR (100 MHz, DMSO-d6) δ (ppm) = 156.9, 126.0, 108.2 15 N NMR (40 MHz, DMSO-d6) δ (ppm) = -11.9, -334.4 Yield: 22 mg of 5 (6% of theory). 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.67 (bs, 2H) 13 C NMR (100 MHz, DMSO-d6) δ (ppm) = 172.9, 147.3, 109.9 15 N NMR (40 MHz, DMSO-d6) δ (ppm) = -191.6, -311.6

[0024] (Example 5) Ethyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridinecarboxylate 4 Synthesis (Step 4 of the overall synthesis)

Chemical Structure

Claims

1. A method for producing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine carboxylate 4 【Chemical 1】 4 (wherein R is C 1-3 alkyl) comprising the steps of: (a) reacting malononitrile with sodium nitrite in the presence of a suitable acid in a suitable solvent under a slight overpressure; (b) reacting the reaction mixture obtained in step (a) with a suitable toluenesulfonic acid derivative to obtain compound 1 [Chemical 2] 1 ; (c) a step of isolating or not isolating compound 1; (d) reacting compound 1 with hydroxylamine in a suitable solvent to obtain compound 2: 【Chemical Formula 3】 2 ; (e) a step of isolating or not isolating compound 2, (f) cyclizing compound 2 while heating to about 70 °C in the presence of a base in a suitable solvent to obtain oxadiazole 3 【Chemical 4】 3 ; (g) removing water from the reaction mixture by evaporation under reduced pressure; (h) removing the p-toluenesulfonate by filtration; (i) condensing compound 3 in the reaction mixture obtained after step (h) in situ with a suitable β-ketoester of the formula 【Chemical Formula 5】 (wherein R is C 1-3 alkyl) in a suitable solvent in the presence of a Lewis acid; (j) isolating compound 4 .

2. The method according to claim 1, wherein step (c) is a step of isolating compound 1.

3. The method according to claim 1 or 2, wherein step (e) is a step of isolating compound 2.

4. The method according to any one of claims 1 to 3, wherein in step (a), hydrochloric acid, hydrobromic acid or acetic acid is used as the suitable acid, and water is used as the solvent.

5. The method according to any one of claims 1 to 4, wherein step (a) is carried out at a temperature of 0 to 25 °C under an overpressure of at most 0.3 bar.

6. The method according to any one of claims 1 to 5, wherein in step (a), hydrobromic acid is used as the suitable acid, and water is used as the solvent at a temperature of 0 to 20 °C.

7. The method according to any one of claims 1 to 6, wherein in step (b), the toluenesulfonic acid derivative is toluenesulfonic anhydride or toluenesulfonyl chloride, and the reaction is carried out at a temperature of 10 to 30 °C.

8. The method according to any one of claims 1 to 7, characterized in that, in step (b), the toluenesulfonic acid derivative is toluenesulfonic acid chloride and the reaction is carried out at a temperature of about 20 °C.

9. The method according to any one of claims 1 to 8, characterized in that, in step (c), compound 1 is precipitated by the addition of an anti-solvent and then isolated by filtration, and the anti-solvent is alcohol.

10. The method according to claim 9, characterized in that the alcohol in step (c) is 2-propanol.

11. The method according to any one of claims 1 to 10, characterized in that, in step (d), the reaction is carried out at a temperature of 10 to 30 °C using ether, alcohol, water, or a mixture thereof as a solvent.

12. The method according to any one of claims 1 to 11, characterized in that, in step (d), the reaction is carried out at a temperature of 20 to 25 °C using tetrahydrofuran, 2-propanol, water, or a mixture thereof as a solvent.

13. The method according to any one of claims 1 to 12, characterized in that, in step (e), compound 2 is precipitated by the addition of an anti-solvent and then isolated by filtration, and the anti-solvent is water.

14. The method according to any one of claims 1 to 13, characterized in that, in step (f), the cyclization is carried out at a temperature of 20 to 100 °C in the presence of triethylamine, an alkali carbonate or an alkali bicarbonate using ether, water or a mixture thereof as the solvent.

15. The method according to claim 14, characterized in that the alkali carbonate is selected from the group consisting of lithium carbonate, sodium carbonate and potassium carbonate, the alkali bicarbonate is selected from the group consisting of lithium bicarbonate, sodium bicarbonate and potassium bicarbonate, the ether is 1,4-dioxane, and the temperature is 60 to 80 °C.

16. The method according to any one of claims 1 to 15, characterized in that, in step (i), the in-situ condensation is carried out at a temperature of 20 to 100 °C in a solvent selected from ether, alcohol, water, or a mixture thereof in the presence of a zinc salt as a Lewis acid.

17. In step (i), the in-situ condensation is carried out at a temperature of 60 to 80 ° C in 1,4-dioxane as the solvent in the presence of zinc dichloride as a Lewis acid, characterized in that the method according to any one of claims 1 to 16.

18. In step (j), compound 4 is precipitated by the addition of an anti-solvent and then isolated by filtration, the anti-solvent being water, characterized in that the method according to any one of claims 1 to 17.

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

Images