A method for synthesizing an intermediate of 2-(1-hydroxyethyl)thiazole-4-carboxylic acid

Abstract

This invention belongs to the field of organic chemistry, specifically relating to a method for synthesizing 2-(1-hydroxyethyl)thiazole-4-carboxylic acid. The preparation method includes the following steps: (1) Compound III undergoes a cyclization reaction with Compound IV to obtain Compound V; (2) Compound V is hydrolyzed to obtain Compound VI. The synthetic route is shown below. This preparation method is convenient to operate, has a simple route, high yield, and requires less reagent, which can greatly shorten the preparation time and cost, reduce waste, and yield a product with high purity, which is beneficial for large-scale production.

Description

Invention Field This invention belongs to the field of organic chemistry, and specifically relates to a method for synthesizing 2-(1-hydroxyethyl)thiazole-4-carboxylic acid. Background Technology

[0001] 2-(1-hydroxyethyl)thiazole-4-carboxylic acid is an important pharmaceutical and chemical intermediate, with the structure shown below: Prior to this invention, there were few reports on methods for synthesizing 2-(1-hydroxyethyl)thiazole-4-carboxylic acid.

[0002] Bray et al. reported a complex and time-consuming route starting from (S)-(-)-2-acetoxypropionyl chloride in Synlett (2010), (4), 599-601. This route involved five steps. For example, the thiolation reaction required large amounts of reagents, had a long reaction time, and low yield; the hydrolysis reaction required 24 hours; and column chromatography purification was necessary during the reaction, which was not conducive to large-scale production. Therefore, it is necessary to develop a convenient, simple, time-efficient, and atom-efficient synthetic route for 2-(1-hydroxyethyl)thiazole-4-carboxylic acid. Summary of the Invention

[0003] This invention provides a preparation method that is convenient to operate, has a simple route, requires less reagents, consumes less time, and has a high yield and high purity.

[0004] The first aspect of this invention discloses a method for preparing intermediate V of 2-(1-hydroxyethyl)thiazole-4-carboxylic acid, comprising the following steps: (1) Compound III undergoes a cyclization reaction with compound IV to give compound V; Wherein, R1 is selected from C1-C4 alkyl or optionally substituted phenyl groups, preferably methyl, ethyl, or tert-butyl; The term "substituted phenyl" above refers to a benzene ring that is substituted by a group selected from the group consisting of: C 1-4 Alkyl, C 1-4 Alkoxy, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, these substituents can be in any possible position on the ring; R2 is selected from C1-C6 alkyl, benzyl, or any substituted benzyl; The C1-C6 alkyl group in R2 is selected from methyl, ethyl, tert-butyl, or pteropentyl; The term "substituted benzyl" refers to a benzene ring that is substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-4Alkoxy, halogen, nitro, cyano, trifluoromethyl—these substituents can be in any possible position on the ring; X is a halogen, which can be selected from chlorine, bromine, or iodine, with bromine being preferred.

[0005] Further, in step (1), the molar ratio of compound III to compound IV is 1: (1-3), preferably 1: (1-2), and more preferably 1: 1.4.

[0006] Further, the solvent used in step (1) is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes or alcohols or water, preferably toluene, water, 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, butanol, and more preferably methanol, ethanol, and isopropanol.

[0007] Further, in step (1), the mass-to-volume ratio of compound III to solvent is 1: (5-20) g / mL, preferably 1: (8-10) g / mL.

[0008] Furthermore, in step (1), the reaction temperature is 50-80℃, preferably 60-70℃, and more preferably 65℃.

[0009] Furthermore, in step (1), the reaction time is 0.5-4 h, preferably 1-2 h.

[0010] A second aspect of the present invention provides a method for preparing compound VI, 2-(1-hydroxyethyl)thiazole-4-carboxylic acid, comprising the following steps: Among them, R 1、 R2 and X are as described in the first aspect above; (1) Compound III undergoes a cyclization reaction with compound IV to give compound V; (2) Compound V was hydrolyzed in the presence of an alkali metal inorganic base to obtain compound VI; Compound V is prepared by a cyclization reaction between compound III and compound IV, as described in the first aspect of this invention.

[0011] Furthermore, the alkali metal inorganic base is selected from NaOH, LiOH, and KOH.

[0012] Further, in step (2), the molar ratio of compound V and base is 1:(2-4), preferably 1:(2-3), and more preferably 1:2.5.

[0013] Further, the solvent used in step (2) is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes or alcohols or water, preferably water, dioxane, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, butanol, more preferably at least one of methanol, ethanol, and isopropanol, and even more preferably one or more of methanol, ethanol, isopropanol, THF, and water.

[0014] Furthermore, a compound of formula III is synthesized through the following steps: (a) Compound II was obtained by reacting 2-hydroxypropionamide with an esterification reagent; (b) Compound II reacts with Lawson's reagent to give compound III; Furthermore, the esterification reagent in step (a) is selected from acid anhydrides or acyl halides; Further, the anhydride is preferably an anhydride with 2 to 20 carbon atoms, such as formic anhydride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pterovaleric anhydride, or benzoic anhydride, etc., and is more preferably acetic anhydride, pterovaleric anhydride, or benzoic anhydride; the acyl halide can be selected from acyl halides with 1 to 10 carbon atoms, such as formyl chloride, acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, isobutyryl chloride, butyryl bromide, isobutyryl bromide, valeric chloride, isovaleric chloride, pterovaleric chloride, n-valeric bromide, benzoyl chloride, or benzoyl bromide, etc., and is more preferably acetyl chloride, acetyl bromide, pterovaleric chloride, benzoyl chloride, or benzoyl bromide.

[0015] Further, in step (a), the molar ratio of compound I to the acylation reagent is 1:(1-2.5), preferably 1:(1-1.5), and more preferably 1:1.2.

[0016] Further, in step (a), an alkali is added to catalyze the reaction, wherein the alkali is selected from 4-dimethylaminopyridine, diisopropylethylamine, triethylamine, pyridine, and preferably triethylamine.

[0017] Further, in step (a), the molar ratio of compound I to base is 1:(1-2.5), preferably 1:(1.5-2.5), and more preferably 1:2.

[0018] Further, the solvent used in step (a) is selected from at least one of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, and haloalkanes, preferably 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, and carbon tetrachloride, and more preferably dichloromethane, dichloroethane, and carbon tetrachloride.

[0019] Further, in step (b), the molar ratio of the compound of formula II to Lawson's reagent is 1:(0.5~1.5), preferably 1:(0.5~1.0), and more preferably 1:0.6.

[0020] Further, step (b) is carried out in an organic solvent selected from at least one of ethers, aromatic hydrocarbons, aliphatic hydrocarbons, and haloalkanes, preferably dioxane, toluene, or THF.

[0021] The present invention has the following beneficial technical effects: 1. This invention provides a novel one-pot method for preparing 2-(1-hydroxyethyl)thiazole-4-carboxylic acid, which is simple to process, has a high yield, and a purity >96%. In particular, after sulfidation, only filtration, rotary evaporation, and pulping purification are required, without the need for column chromatography to separate the product, which facilitates large-scale production.

[0022] 2. The inventors unexpectedly discovered that compound III can react directly with compound IV in a solvent to obtain compound V without the need for additional acid or base. This "one-pot" method hydrolyzes the acetyl group during the cyclization reaction. In existing technologies, such as Synlett (2010), (4), 599-601, and Chemistry Letters (1995), (1), 45-6, additional trifluoroacetic anhydride is required for dehydration to achieve cyclization, which is cumbersome. Furthermore, the hydroxyl protecting group (e.g., acetyl) and ester group (e.g., ethyl) are hydrolyzed under the action of a base, while in this invention, only the ester group needs to be hydrolyzed. Using the route of this invention can greatly shorten the preparation time and cost, reduce waste, and facilitate large-scale production.

[0023] 3. The raw materials and reagents required for this invention are simple and readily available, avoiding the use of flammable epoxide and ammonia, thus reducing the overall production cost and improving safety. Attached Figure Description

[0024] Figure 1 Compound 5 of Example 3 1 H NMR spectrum.

[0025] Figure 2 Example 4: 2-(1-hydroxyethyl)thiazole-4-carboxylic acid 1 H NMR spectrum.

[0026] Figure 3 The HPLC chromatogram of 2-(1-hydroxyethyl)thiazole-4-carboxylic acid is shown in Example 4. Detailed Implementation

[0027] The beneficial effects of the present invention will now be further described through the following embodiments. It should be understood that these embodiments are for illustrative purposes only and do not limit the scope of the present invention. At the same time, obvious changes and modifications made by those skilled in the art according to the present invention are also included within the scope of the present invention.

[0028] Example 1 Weigh 20.9 g (0.23 mol) of compound 1 into a three-necked flask, add 120 mL of DCM, and then cool the system to 0 °C. Begin adding 27.59 g (0.27 mol) of acetic anhydride dropwise, followed by 45.49 g (0.45 mol) of triethylamine. Stir the reaction overnight. Add 1 mol / L hydrochloric acid and extract with DCM. Dry the organic phase with anhydrous sodium sulfate. Rotate the organic phase to dryness to obtain 20 g of a colorless oily liquid, with a yield of 68%. No further purification is required; the product is directly used in the next step.

[0029] Example 2 20 g (0.15 mol) of compound 2 and 37 g (0.09 mol) of Lawson's reagent were placed in a three-necked flask, 200 mL of THF was added, the mixture was purged with nitrogen three times, heated to 60 °C, and stirred for 2 h. The precipitated solid was filtered, and the filtrate was evaporated to dryness. The mixture was extracted with dichloromethane and brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under reduced pressure to give 17 g of a pale yellow solid, with a yield of 77%. No further purification was required, and the product was directly used in the next step.

[0030] Example 3 17 g (0.12 mol) of compound 3 and 31.4 g (0.17 mol) of methyl bromide pyruvate were added to a three-necked flask, followed by 170 mL of methanol. The mixture was heated to 65 °C and stirred for 2 h. The precipitated solid was filtered, and the filtrate was evaporated to dryness. Ethyl acetate was added and the mixture was beaten to give 15 g of a pale yellow solid, with a yield of 69.4%. No further purification was required; the product was directly used in the next step.

[0031] Example 4 15 g (0.08 mol) of compound 5 was added to 75 mL of methanol and placed in a three-necked flask. 8.0 g (0.2 mol) of sodium hydroxide was dissolved in 15 mL of water and added to the flask. The mixture was heated to 60 °C and reacted for 3 h. The precipitated solid was filtered. Ethyl acetate was added for extraction, and the pH was adjusted to 1-2 with 1 mol / L hydrochloric acid. 8.74 g of a white solid precipitated, yielding 63% of the solid with a purity of 96.5%.

Claims

1. A method for preparing intermediate V, comprising the following steps: (1) the cyclization reaction of compound III with compound IV to obtain intermediate V; wherein, The molar ratio of compound III to compound IV is 1:(1-3); the solvent used is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes or alcohols or water; wherein R1 is selected from C1-C4 alkyl or optionally "substituted phenyl"; wherein the "substituted phenyl" is a benzene ring substituted by a group selected from C1-4 alkyl, C1-4 alkoxy, halogen, nitro, cyano, trifluoromethyl, or trifluoromethoxy. R2 is selected from C1-C6 alkyl, benzyl or any substituted benzyl; wherein, the "substituted benzyl" means that the benzene ring is substituted by a group selected from C1-3 alkyl, C1-4 alkoxy, halogen, nitro, cyano or trifluoromethyl; X is selected from chlorine, bromine, or iodine.

2. The preparation method according to claim 1, characterized in that: The C1-C4 alkyl group in R1 is selected from methyl, ethyl, and tert-butyl. And / or, the C1-C6 alkyl group in R2 is selected from methyl, ethyl, tert-butyl, or pteropentyl.

3. The preparation method according to claim 1, characterized in that: The reaction temperature is 50-80℃.

4. The preparation method according to claim 3, characterized in that: The reaction time is 0.5-4 h.

5. A method for preparing compound VI, characterized in that, The compound VI is 2-(1-hydroxyethyl)thiazole-4-carboxylic acid, and the preparation method includes the following steps: Wherein, the substituents R1, R2 and X are defined as defined in claim 1; (1) Compound III undergoes a cyclization reaction with Compound IV to give intermediate V; wherein the molar ratio of Compound III to Compound IV is 1: (1-3); the solvent used is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes or alcohols or water; (2) Intermediate V was hydrolyzed in the presence of an alkali metal inorganic base to obtain compound VI.

6. The preparation method according to claim 5, characterized in that: The C1-C4 alkyl group in R1 is selected from methyl, ethyl, and tert-butyl. And / or, the C1-C6 alkyl group in R2 is selected from methyl, ethyl, tert-butyl, or pteropentyl.

7. The preparation method according to claim 5, characterized in that: The reaction temperature is 50-80℃.

8. The preparation method according to claim 7, characterized in that: The reaction time is 0.5-4 h.

9. The preparation method according to any one of claims 1 to 8, characterized in that: In step (1), the molar ratio of compound III to compound IV is 1: (1-2).

10. The preparation method according to any one of claims 1 to 8, characterized in that: In step (1), the molar ratio of compound III to compound IV is 1:1.

4.

11. The preparation method according to any one of claims 1 to 8, characterized in that: The solvent used in step (1) cyclization reaction is selected from one or more of toluene, water, 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, and butanol.

12. The preparation method according to any one of claims 1 to 8, characterized in that: The cyclization reaction in step (1) uses one or more of methanol, ethanol, and isopropanol as the solvent.

13. The preparation method according to any one of claims 1 to 8, characterized in that: In step (1), the mass-to-volume ratio of compound III to solvent is 1: (5-20) g / mL.

14. The preparation method according to any one of claims 1 to 8, characterized in that: In step (1), the mass-to-volume ratio of compound III to solvent is 1: (8-10) g / mL.

15. The preparation method according to any one of claims 1 to 8, characterized in that: The cyclization reaction in step (1) is carried out at 60-70℃.

16. The preparation method according to any one of claims 1 to 8, characterized in that: The cyclization reaction in step (1) is carried out at 65°C.

17. The preparation method according to any one of claims 1 to 8, characterized in that: The cyclization reaction in step (1) takes 1-2 hours.

18. The preparation method according to claim 5, characterized in that: In step (2), the alkali metal inorganic base is selected from NaOH, LiOH or KOH.

19. The preparation method according to any one of claims 5 to 8, characterized in that: According to the preparation method of claim 3, the molar ratio of intermediate V and base in step (2) is 1:(2-4).

20. The preparation method according to any one of claims 5 to 8, characterized in that: According to the preparation method of claim 3, the molar ratio of intermediate V and base in step (2) is 1:(2-3).

21. The preparation method according to any one of claims 5 to 8, characterized in that: According to the preparation method of claim 3, the molar ratio of intermediate V and base in step (2) is 1:2.

5.

22. The preparation method according to any one of claims 5 to 8, characterized in that: The solvent used in step (2) is selected from one or more of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, haloalkanes, alcohols, or water.

23. The preparation method according to claim 5, characterized in that: The solvent used in step (2) is selected from one or more of the following: water, dioxane, THF, dichloromethane, dichloroethane, carbon tetrachloride, methanol, ethanol, propanol, isopropanol, and butanol.

24. The preparation method according to any one of claims 5 to 8, characterized in that: The solvent used in step (2) is selected from one or more of methanol, ethanol, isopropanol, THF, and water.

25. The preparation method according to claim 1 or 5, characterized in that: X is bromine or iodine; R1 is selected from C1-C4 alkyl groups; R2 is selected from C1-C6 alkyl groups; Furthermore, in step (1), The molar ratio of compound III to compound IV is 1: (1-3). The solvent used is an alcohol; The reaction temperature is 50-80℃; and The reaction time is 0.5-4 h.

26. The preparation method according to claim 1 or 5, characterized in that: X is bromine or iodine; R1 is selected from C1-C4 alkyl groups; R2 is selected from C1-C6 alkyl groups; Furthermore, in step (1), The molar ratio of compound III to compound IV is 1: (1-2); The solvents used are selected from: methanol, ethanol, propanol, isopropanol, and butanol; The reaction temperature is 60-70℃; and The reaction time is 0.5-4 h.

27. The preparation method according to claim 1 or 5, characterized in that: X is bromine; R1 is a methyl group; R2 is a methyl group; Furthermore, in step (1), The molar ratio of compound III to compound IV is 1: (1-2); The solvent used is methanol; The reaction temperature is 60-70℃; and The reaction time is 0.5-4 h.

28. The preparation method according to any one of claims 1 to 8, characterized in that: Compound III was prepared by a method comprising the following steps: (a) Compound I was reacted with an esterifying agent to obtain compound II; (b) Compound II reacts with Lawson's reagent to give compound III.

29. The preparation method according to claim 28, characterized in that: Step (a) uses compound I as a starting material and reacts it with an esterification reagent to satisfy one or more of the following conditions: 1) In step (a), the esterification reagent is selected from acid anhydrides or acyl halides; And / or, 2) In step (a), the molar ratio of compound I to the esterifying agent is 1:(1-2.5). 3) Add an alkali to the reaction in step (a); 4) The solvent used in step (a) is selected from at least one of esters, ethers, aromatic hydrocarbons, aliphatic hydrocarbons, and haloalkanes.

30. The preparation method according to claim 29, characterized in that: The acid anhydride is an acid anhydride with 2 to 20 carbon atoms; and / or, the acyl halide is an acyl halide with 1 to 10 carbon atoms.

31. The preparation method according to claim 29, characterized in that: The anhydride is selected from the group consisting of: formic anhydride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, isovaleric anhydride, pterovaleric anhydride, or benzoic anhydride; and / or the acyl halide is selected from the group consisting of: formyl chloride, acetyl chloride, acetyl bromide, propionyl chloride, propionyl bromide, butyryl chloride, isobutyryl chloride, butyryl bromide, isobutyryl bromide, valeric chloride, isovaleric chloride, pterovaleric chloride, n-valeric bromide, benzoyl chloride, or benzoyl bromide.

32. The preparation method according to claim 29, characterized in that: The acid anhydride is acetic anhydride, pivalic anhydride, or benzoic anhydride; and / or the acyl halide is acetyl chloride, acetyl bromide, pivalic acyl chloride, benzoyl chloride, or benzoyl bromide.

33. The preparation method according to claim 28, characterized in that: In step (a), the molar ratio of compound I to the esterifying agent is 1:(1-1.5).

34. The preparation method according to claim 28, characterized in that: In step (a), the molar ratio of compound I to the esterifying agent is 1:1.

2.

35. The preparation method according to claim 29, characterized in that: The base is selected from 4-dimethylaminopyridine, diisopropylethylamine, triethylamine, and pyridine.

36. The preparation method according to claim 29, characterized in that: The base is triethylamine.

37. The preparation method according to claim 29, characterized in that: In step (a), the molar ratio of compound I to the base is 1:(1-2.5).

38. The preparation method according to claim 29, characterized in that: In step (a), the molar ratio of compound I to the base is 1:(1.5-2.5).

39. The preparation method according to claim 29, characterized in that: In step (a), the molar ratio of compound I to the base is 1:

2.

40. The preparation method according to claim 28, characterized in that: The solvent used in step (a) is selected from 1,4-dioxane, DMF, THF, dichloromethane, dichloroethane, and carbon tetrachloride.

41. The preparation method according to claim 28, characterized in that: The solvent used in step (a) is dichloromethane, dichloroethane, or carbon tetrachloride.

42. The preparation method according to claim 28, characterized in that: In step (b), compound II reacts with Lawson's reagent to satisfy one or more of the following conditions: 1) In step (b), the molar ratio of compound II to Lawson's reagent is 1:(0.5~1.5). 2) Step (b) is carried out in an organic solvent.

43. The preparation method according to claim 28, characterized in that: In step (b), the molar ratio of compound II to Lawson's reagent is 1:(0.5~1.0).

44. The preparation method according to claim 28, characterized in that: In step (b), the molar ratio of compound II to Lawson's reagent is 1:0.

6.

45. The preparation method according to claim 42, characterized in that: In step (b), the organic solvent is selected from at least one of ethers, aromatic hydrocarbons, aliphatic hydrocarbons, and haloalkanes.

46. ​​The preparation method according to claim 42, characterized in that: In step (b), the organic solvent is selected from dioxane, toluene, and THF.

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