Preparation method of halogenated imidazole derivative

Abstract

The invention provides a novel method for preparing a halogenated imidazole derivative as shown in a formula IIA, the method takes a compound as shown in a formula IV as a raw material for the first time, the compound as shown in the formula IIA is generated through a ring-opening reaction and a deamination reaction, the reaction conditions are simple and mild, the process steps are simple, the operability is high, post-treatment is convenient, the yield is high, and the method is very suitable for large-scale industrial production. # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical chemistry and relates to a method for preparing a halogenated imidazole derivative. Background Art

[0002] Etomidate, chemically known as R-(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-carboxylic acid ethyl ester, is an intravenous anesthetic drug characterized by rapid onset, short duration of action, rapid recovery, and mild inhibitory effects on cardiovascular and respiratory function. It is mainly used clinically for induction of anesthesia and outpatient surgical anesthesia. However, studies have found that while etomidate exerts its anesthetic effect, it may inhibit 11β-hydroxylase, thereby reducing the secretion of cortisol and / or corticosterone. Therefore, long-term use of etomidate is potentially fatal.

[0003] WO201759827A1 reports an etomidate derivative shown in formula I, which not only has good anesthetic activity, rapid onset and short duration of action, but also has little inhibitory effect on the secretion of cortisol and / or corticosterone, thus having good anesthetic effect and safety. The document also reports a method for preparing the etomidate derivative using the intermediate compound shown in formula II as a raw material.

[0004]

[0005] In particular, the synthesis of the fluorinated intermediate compound represented by Formula IIA' or IIB' is carried out in the art by the method shown in WO201759827A1, and the synthesis route is illustrated as follows:

[0006]

[0007] However, the synthesis methods all involve the use of HBF4 solution and light conditions. The HBF4 solution is fluoroboric acid, which is a strong inorganic acid, toxic and extremely corrosive. It has a certain degree of corrosiveness to conventional chemical reaction containers. In addition, the light reaction conditions are difficult to control, and such reaction conditions are not suitable for large-scale production.

[0008] Therefore, there is an urgent need in the art for a new method for synthesizing the halogenated imidazole derivative intermediate shown above. Summary of the invention

[0009] As mentioned above, the methods for preparing the fluoroimidazole derivatives represented by Formula IIA' or IIB' in the prior art all involve introducing fluorine through fluorination in the last step, but the reaction conditions are relatively high and are not suitable for industrial production.

[0010] The present invention provides a new synthesis idea and route, that is, directly using fluorinated raw materials, and then introducing other functional groups on this basis, thereby avoiding the harsh reaction conditions of introducing fluorine by fluorinating the imidazole ring. The reaction conditions of the present invention are simple and mild, the process steps are simple, and the operability is strong. At the same time, the synthesis route is simple, the operation is simple, the post-treatment is convenient, the yield is high, and it is very suitable for large-scale industrial production.

[0011] Based on the inventive concept of directly using fluorinated raw materials, the inventors of this application have tried dozens of synthetic routes, but none of them have successfully achieved the preparation of the target compound. Finally, it is proposed for the first time to use the compound shown in Formula IV as the raw material, to prepare the compound shown in Formula III through a ring-opening reaction, and to prepare the target compound through a deamination reaction of the compound shown in Formula III.

[0012] In one aspect, the present invention provides a method for preparing a compound of formula IIA, comprising

[0013] The compound represented by formula III is subjected to a deamination reaction to prepare the compound represented by formula IIA:

[0014]

[0015] Wherein, Y is halogen; and R 1 is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10 The substituents of the aryl group are substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 Aryl.

[0016] In another aspect, the present invention provides a method for preparing a compound represented by formula III, comprising

[0017] The compound represented by formula IV is subjected to a ring-opening reaction to prepare the compound represented by formula III:

[0018]

[0019] Where Y and R 1 As defined above.

[0020] In another aspect, the present invention provides a compound as shown in formula III',

[0021]

[0022] Where Y and R 1 As defined above, M- It is an acid ion, preferably a chloride ion, a bromide ion, a nitrate ion, a nitrite ion, a dihydrogen phosphate ion, a hypophosphite ion, a formate ion, an acetate ion, a propionate ion or a hydrogen sulfate ion, and more preferably a chloride ion, a dihydrogen phosphate ion, a hypophosphite ion or a hydrogen sulfate ion.

[0023] In another aspect, the present invention provides a compound or a salt thereof as shown below,

[0024]

[0025] In another aspect, the present invention provides a method for preparing a compound of formula IA, comprising using one of the aforementioned methods,

[0026]

[0027] Where Y and R 1 As defined above. DETAILED DESCRIPTION

[0028] the term

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0030] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0031] The term "substituted" as used herein means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0032] The term "alkyl" refers to an aliphatic hydrocarbon saturated group, which may be a branched or straight chain alkyl group. Depending on the structure, an alkyl group may be a monovalent group or a divalent group (i.e., an alkylene group). The term "C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc. In some embodiments, the alkyl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.

[0033] The term "alkenyl" refers to a general term for hydrocarbons containing a carbon-carbon double bond in the molecule and is an unsaturated aliphatic hydrocarbon group. 2-6 The term "alkenyl" refers to a straight or branched unsaturated hydrocarbon group having at least one carbon-carbon double bond and 2 to 6 carbon atoms, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0034] The term "alkynyl" refers to a general term for hydrocarbons containing a carbon-carbon triple bond in the molecule and is an unsaturated aliphatic hydrocarbon group. 2-6 The term "alkynyl" refers to a straight or branched unsaturated hydrocarbon group having at least one carbon-carbon triple bond and 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0035] The term "aryl" refers to an all-carbon monocyclic or polycyclic aromatic group having a conjugated π electron system. 6-10 "Aryl" refers to an aromatic group containing 6-10 carbon atoms. Examples of aryl groups may include phenyl, naphthyl, and the like. In some embodiments, the aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.

[0036] The term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In some embodiments, the cycloalkyl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents.

[0037] The term "alkoxy" refers to an alkyl-O- group, wherein alkyl is as defined herein. 1-6 "Alkoxy" refers to a group of the formula -OC 1-6 A saturated monovalent hydrocarbon radical of an alkyl group, wherein the term "C 1-6 "Alkyl" is as defined above, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.

[0038] The term "carbonyl" refers to an organic functional group -C(=O)- formed by a double bond between carbon and oxygen atoms.

[0039] The term "alkoxycarbonyl" or "alkoxycarbonyl" refers to an alkoxy-C(=O)- group, i.e., the group is attached to the rest of the compound through a carbonyl group. 2-7"Alkoxycarbonyl" refers to a C-terminal group attached to the rest of the molecule through a carbonyl bond. 1-6 Alkoxy, wherein the term "C 1-6 The “alkoxy” is as defined above, for example methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, n-hexyloxycarbonyl and the like.

[0040] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0041] The term "cyano" refers to a group -CN in which a carbon atom and a nitrogen atom are connected by a triple bond.

[0042] The term "optionally substituted" or "optionally substituted by" means that the referenced group may or may not be substituted.

[0043] The term "alcohols" refers to a class of organic compounds formed by replacing one or more hydrogen atoms in a hydrocarbon molecule with a hydroxyl group, such as methanol, ethanol, propanol, butanol, pentanol, hexanol, etc.

[0044] In this specification, "%" when modifying, for example, a chemical substance, refers to the mass percentage of the chemical substance as a solute in the solution formed after it is dissolved in a solvent. Unless otherwise specified, the solvent is water. For example, "50% hydroxylamine aqueous solution" means that hydroxylamine as a solute forms an aqueous solution with a mass percentage of 50% in water as a solvent. For another example, "50% hypophosphorous acid" or "50% hypophosphorous acid solution" means that hypophosphorous acid as a solute forms an aqueous solution with a mass percentage of 50% in water as a solvent. Unless otherwise specified, the solutions mentioned in this specification all use water as a solvent.

[0045] The term "about" in the context of the present invention means within 10%, suitably within 5%, in particular within 1% of a given value or range.

[0046] In some embodiments, the method for preparing the compound of formula IIA comprises subjecting the compound of formula III to a deamination reaction to prepare the compound of formula IIA. In some embodiments, the method for preparing the compound of formula IIA comprises subjecting the compound of formula IV to a ring-opening reaction to prepare the compound of formula III, and subjecting the compound of formula III to a deamination reaction to prepare the compound of formula IIA.

[0047] In Formula IIA, Formula III, Formula III', and Formula IV of the present specification, Y is halogen; and R 1 is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10The substituents of the aryl group are substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 Aryl.

[0048] In some embodiments, Y is fluorine, fluorine, bromine, or iodine. In some embodiments, Y is fluorine.

[0049] In some embodiments, R 1 C 1-6 In some embodiments, R 1 It is ethyl.

[0050] In some embodiments, Y is fluorine, R 1 C 1-6 alkyl.

[0051] In some embodiments, the compound of formula III is subjected to a deamination reaction to prepare the compound of formula IIA. In some embodiments, the deamination reaction comprises subjecting the compound of formula III to a diazotization reaction and a reduction reaction of a diazonium salt.

[0052] In some embodiments, the diazotization reaction and the reduction reaction of the diazonium salt are to carry out a diazotization reaction and a reduction reaction of the diazonium salt by subjecting the compound represented by Formula III to a diazotization reagent in the presence of a reducing agent; or the diazotization reaction is to carry out a diazotization reaction of the compound represented by Formula III to a diazotization reagent to generate a diazonium salt, and then to carry out a reduction reaction of the diazonium salt in the presence of a reducing agent.

[0053] In some embodiments, the diazotization reagent is a nitrous acid solution, and the diazotization reagent is selected from one or more of sodium nitrite, potassium nitrite, isopropyl nitrite, n-butyl nitrite, tert-butyl nitrite, n-amyl nitrite, tert-butyl nitrite, and isoamyl nitrite. In some embodiments, the diazotization reagent is sodium nitrite.

[0054] In some embodiments, the diazotization reaction and the reduction reaction of the diazonium salt are carried out at low temperature, preferably not more than 10°C, preferably -15 to 10°C, preferably -15 to 5°C, preferably -10 to -5°C.

[0055] In some embodiments, an acidic solvent is introduced into the reaction system to provide acidic reaction conditions. The acidic solution is selected from one or more of nitric acid, sulfuric acid, hydrochloric acid, phosphoric acid, hypophosphorous acid, formic acid, acetic acid, propionic acid, and hydrobromic acid. In some embodiments, the acidic solution is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, or hypophosphorous acid. In some embodiments, the acidic solution is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, or hypophosphorous acid. In some embodiments, the acidic solution is hydrochloric acid or hypophosphorous acid. In some embodiments, the acidic solution is hypophosphorous acid, such as 50% hypophosphorous acid solution.

[0056] In some embodiments, an organic solvent is introduced into the reaction system. The inventors found that the introduction of an organic solvent can promote the diazotization reaction and improve the yield. It is speculated that the organic solvent helps the dissolution of the diazotization reaction raw materials and / or products in the reaction system. In some embodiments, the organic solvent is preferably an organic solvent that is miscible with water. In some embodiments, the organic solvent is selected from one or more of tetrahydrofuran (THF), acetonitrile (ACN), 1,4-dioxane, low-level esters (such as ethyl acetate, isopropyl acetate), etc., preferably selected from one or more of tetrahydrofuran (THF), acetonitrile (ACN), and 1,4-dioxane, preferably tetrahydrofuran (THF).

[0057] In some embodiments, the reducing agent used in the reduction reaction of the diazonium salt can be selected from an organic reagent or an inorganic reagent. In some embodiments, the organic reagent can be selected from one or more of alcohols (e.g., methanol, ethanol), HCHO / NaOH, formic acid, hydroquinone, glucose / NaOH, and NaBH4. In some embodiments, the inorganic reagent can be selected from one or more of H3PO2, SnCl2, Na2S2O4, FeSO4, and zinc powder. In some embodiments, the reducing agent is selected from an inorganic reagent. In some embodiments, the reducing agent is H3PO2. In some embodiments, the reducing agent is 10 to 50% H3PO2 solution, preferably about 50% H3PO2 solution.

[0058] In some embodiments, a catalyst is further added to the reduction reaction of the diazonium salt. In some embodiments, the catalyst is a metal copper compound, preferably one or more selected from cuprous oxide, cuprous chloride, and cupric sulfate. In some embodiments, after adding the catalyst, the reaction efficiency is significantly improved, the reaction time is shortened, and the product yield can be improved.

[0059] In some embodiments, when a large amount of deamination process is performed, a small amount of foam is observed to be generated and the yield of the target product is reduced. The introduction of the aforementioned organic solvent and / or catalyst can effectively promote the reaction and improve the reaction yield.

[0060] In some embodiments, the reduction reaction of the diazonium salt uses H3PO2 as a reducing agent and cuprous oxide as a catalyst.

[0061] In some embodiments, the diazonium salt has a structure as shown in Formula III',

[0062]

[0063] Where Y and R 1 As defined above, M - It is an acid radical ion. M- varies depending on the reagent used in the diazotization reaction.

[0064] In some embodiments, M- is chloride, bromide, nitrate, nitrite, dihydrogen phosphate, hypophosphite, formate, acetate, propionate, or bisulfate. - It is a chloride ion, a dihydrogen phosphate ion, a hypophosphite ion or a hydrogen sulfate ion.

[0065] In some embodiments, the compound shown in formula IV is subjected to a ring-opening reaction to prepare the compound shown in formula III. In some embodiments, the ring-opening reaction is carried out in the presence of hydroxylamine hydrochloride / base. In some embodiments, the base is selected from an organic base or an inorganic base. In some embodiments, the organic base can be selected from one or more of triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), and pyridine. In some embodiments, the inorganic base can be selected from one or more of sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, sodium hydroxide, and potassium hydroxide.

[0066] In some embodiments, the ring-opening reaction is performed in the presence of an aqueous hydroxylamine solution.

[0067] In some embodiments, the ring-opening reaction is carried out at 20-75°C, preferably at 20-50°C, preferably at 30-40°C, preferably at about 35-40°C.

[0068] In some embodiments, the molar ratio of the compound of formula IV to hydroxylamine is 1:1 to 10, preferably 1:2 to 7, preferably 1:3 to 5, and preferably about 1:4.

[0069] In some embodiments, the molar ratio of the compound of formula IV to the base is 1:1 to 20, preferably 1:2 to 16, preferably 1:2 to 10, and preferably about 1:5.

[0070] In some embodiments, the ring-opening reaction is carried out in an organic solvent. In some embodiments, the organic solvent is selected from one or more of alcohols (e.g., ethanol), N,N-dimethylacetamide (DMA), and N,N-dimethylformamide (DMF). In some embodiments, the organic solvent is N,N-dimethylformamide (DMF). In particular, when the organic solvent is DMF, the product has a high yield, high purity, and simple post-processing.

[0071] In some embodiments, Formula IV is Formula IVA:

[0072]

[0073] In some embodiments, the compound of formula IVA is prepared as follows:

[0074]

[0075] In some embodiments, the target compound of the present invention can be synthesized using 2-aminopyrimidine, a common industrial reagent, as a raw material. The raw material is cheap and readily available, the process route is short, the reaction conditions are mild, the process is highly operable, and the yield is high, which is very suitable for industrial mass production. Specifically, 2-aminopyrimidine first generates a compound shown in formula V, and then forms a ring to generate a compound shown in formula IVA.

[0076] In some embodiments, the reactants reacted with 2-aminopyrimidine in the above synthetic route, and R in Formula IVA and Formula V 1 As mentioned above, specifically, it is optionally substituted with one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10 Substituents of the aryl group substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 In some embodiments, R in Formula IVA and Formula V is 1 C 1-6 Alkyl, more specifically ethyl.

[0077] The compounds represented by the aforementioned formula V, formula IV, formula IVA, formula III, and formula III' are all important intermediates for synthesizing the compound represented by formula IIA, especially important intermediates for synthesizing the compound represented by formula IIA wherein Y is F.

[0078] In some embodiments, the compound shown in Formula IIA can be used as a raw material to prepare the etomidate derivative shown in Formula IA.

[0079]

[0080] Where Y and R 1 As defined above.

[0081] Example

[0082] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application. In the absence of conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. If not otherwise specified, the reagents used in the embodiments are conventional commercially available reagents. If not otherwise specified, the hypophosphorous acid used in the embodiments is 50% hypophosphorous acid, and the phosphoric acid is 80% phosphoric acid.

[0083] Example 1 Preparation of 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester

[0084]

[0085] Step 1:

[0086] Preparation of 3,3,3-trifluoro-2-(pyrimidin-2-imino)propionic acid ethyl ester

[0087] Dissolve 2-aminopyrimidine (500.0g) in dichloromethane (10.0L), add ethyl 3,3,3-trifluoropyruvate (938g) dropwise, the system becomes turbid, and reacts at room temperature for 1h. Add thionyl chloride (656.7g) dropwise to the above system, the system becomes clear, and reacts by stirring for 0.5h. Add pyridine (861.7g) dropwise to the reaction system under an ice-water bath, after the dripping is complete, allow the system to slowly warm to room temperature, and react by stirring for 6h. Evaporate the solvent, add isopropyl ether (2.5L), stir for 0.5h, and filter, and rinse the filter cake three times with isopropyl ether (333mL×3). The mother liquor is distilled under reduced pressure to obtain the target compound (1151.7g, yield 88.6%) as a nearly colorless to light yellow oil. 1 H NMR (400MHz, CDCl3) δ8.76-8.75(d,J=5.2Hz,1H),7.27-7.24(t,J=5.2Hz,2H),4.28-4.22(q,J=7.2Hz,2H),1.20–1.16(t,J=7.2Hz,3H).

[0088] Step 2:

[0089] Preparation of 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester

[0090] Dissolve ethyl 3,3,3-trifluoro-2-(pyrimidine-2-imino)propionate (1130 g) in isopropyl ether (9.0 L), add trimethyl phosphite (567 g) dropwise at -5°C, control the temperature below 15°C, and slowly warm to room temperature after the addition is complete. React for 6 hours, and solid will precipitate in the reaction solution. Filter by suction to obtain the target compound (569.5 g, yield 59.6%) as a light yellow solid. ESI[M+H] + =210.20.

[0091] Example 2 Preparation of ethyl 2-amino-4-fluoro-1H-imidazole-5-carboxylate

[0092]

[0093] Example 2.1

[0094] At room temperature, ethyl 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylate (533 g) was placed in DMF (2.7 L), and a 50% aqueous solution of hydroxylamine (601.5 mL) was added dropwise, and the temperature was controlled not to exceed 40°C. After the addition was completed, the reaction solution was heated to 40°C. After the reaction was complete as monitored by TLC, water (5.33 L) was added to precipitate a solid, stirred for 30 min, filtered under reduced pressure, and the filter cake was washed with water (400 mL × 3) to obtain the target compound (353.6 g, yield 80.1%) as a white solid. ESI [MH] - = 172.20.

[0095] Example 2.2

[0096] At room temperature, 3-fluoroimidazole [1,2-a] pyrimidine-2-carboxylic acid ethyl ester (400 mg) was dissolved in DMA (15 mL), hydroxylamine hydrochloride (1.33 g) and sodium carbonate (2.03 g) were added, the temperature was raised to 40 ° C and stirred, and after TLC monitoring, the reaction raw materials disappeared, water was added and dichloromethane was extracted and rotary evaporated to obtain 100 mg of white solid. TLC detected the target compound and trace impurities, and MS detected molecular ion peaks of 172.2 and 188.15.

[0097] Example 2.3

[0098] At room temperature, 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester (15g) was suspended in ethanol (300mL), and 50% hydroxylamine aqueous solution (19g) was added dropwise, and the temperature was raised to 40°C after the addition. The reaction was allowed to proceed overnight, and the reaction raw materials disappeared as monitored by TLC. 150mL of n-heptane was added, and the mixture was slurried and filtered to obtain 13.88g of a white solid. Water was added to slurry, and the mixture was dried to obtain 12.12g of a white solid. MS detected molecular ion peaks of 172.2 and 223.18.

[0099] Comparative Example 2.1

[0100]

[0101] 3-Fluoroimidazolo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester (50 mg) and hydrazine hydrate (11 mg) were dissolved in ethanol (0.5 mL) and heated to reflux. After 5 hours, the reaction was monitored by TLC. The starting material disappeared. The molecular weight obtained by LC-MS was 222, which was presumed to be a fluorine-substituted product.

[0102] Examples 2.4-2.11 and Comparative Example 2.2:

[0103] The examples and comparative examples in Table 1 below were carried out with reference to the above-mentioned Example 2.1 and Comparative Example 2.1, respectively. The specific feed materials, reaction conditions and results are shown in Table 1 below:

[0104] Table 1

[0105]

[0106]

[0107] Example 3 Preparation of 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester

[0108]

[0109] Example 3.1

[0110] Under ice-salt bath, ethyl 2-amino-4-fluoro-1H-imidazole-5-carboxylate (10.0 g) was suspended in a mixed solution of 50% hypophosphorous acid (200 mL) and phosphoric acid (8 mL), and an aqueous solution (17.5 ml) containing NaNO2 (4.38 g) was added, and the mixture was reacted under ice bath for 6 h. The reaction was monitored by TLC. After the reaction was complete, it was neutralized with a saturated sodium bicarbonate solution, extracted with ethyl acetate (100 ml × 3), and the organic layers were combined, washed with sodium bicarbonate solution and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound (6.57 g, yield 71.9%) was obtained as a white solid by hot slurrying with ethyl acetate / n-heptane, filtering, and drying. ESI [MH] - = 157.20.

[0111] Example 3.2

[0112] At -15°C, ethyl 2-amino-4-fluoro-1H-imidazole-5-carboxylate (298.0 g) was suspended in a mixed solvent of 50% hypophosphorous acid (4.77 L) and tetrahydrofuran (1.5 L), and an aqueous solution (523 ml) containing NaNO2 (130 g) was added. The temperature was controlled between -15-5°C. TLC confirmed the disappearance of the starting material. The reaction solution was added to a 0°C solution of 50% hypophosphorous acid (3 L) containing cuprous oxide (12.3 g), and the temperature was controlled not to exceed 10°C. After the addition, the reaction was monitored by TLC until the diazonium salt disappeared, and salt (1.0 kg) and water (2 L) were added, and ethyl acetate (2.4 L × 4) was used for extraction, and the organic phases were combined and washed with 5% sodium bicarbonate (3 L × 3). When emulsification occurred, the mixture was filtered with Florisil pad, and the collected organic phases were combined, washed with 20% hydrochloric acid (3.16 L), and washed with 20% sodium chloride (3 L). The organic phase was concentrated to dryness under reduced pressure, and ethyl acetate / n-heptane (600 mL: 1.8 L) was added for slurrying, filtered, and dried to obtain the target compound (174 g, yield 63.9%) as a white solid. ESI [MH] - = 157.20.

[0113] Comparative Example 3.1

[0114]

[0115] 5-Fluoroimidazole [2,1-b] thiazole-6-carboxylic acid ethyl ester (100 mg) and Raney Ni (110 mg) were added to ethanol (10 mL) and refluxed. The raw material disappeared by TLC detection. The LC-MS molecular weight was 337.25 and 373.15, which was presumed to be the 2M+1 peak. No 4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester was generated. In view of the poor tolerance of this substrate to Raney Ni, fluorine was easily removed during desulfurization, and this process was not further studied.

[0116] Examples 3.3 to 3.13

[0117] The examples in Table 2 below are carried out with reference to the above Example 3.1, and the specific feeding, reaction conditions and results are shown in Table 2 below:

[0118]

[0119]

[0120] Note: The "vol" used for solvents or solutions in Table 2 above refers to the relative amount of the raw material. For example, when the raw material feed amount is 1.0g, 5vol means 5 times the volume, in ml, i.e. 5.0ml.

[0121] Example 4 Preparation of ethyl 2-amino-4-chloro-1H-imidazole-5-carboxylate

[0122] The compound was prepared according to the method of Example 2.1, but 3-chloroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester was used instead of 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester to obtain 2-amino-4-chloro-1H-imidazole-5-carboxylic acid ethyl ester. (ES, m / z): [M-1] = 190.03, 192.03.

[0123] Example 5 Preparation of 4-chloro-1H-imidazole-5-carboxylic acid ethyl ester

[0124] The compound was prepared according to the method of Example 3.1, but 2-amino-4-chloro-1H-imidazole-5-carboxylic acid ethyl ester was used instead of 2-amino-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to obtain 4-chloro-1H-imidazole-5-carboxylic acid ethyl ester. (ES, m / z): [M-1] = 173.02, 175.02.

[0125] Example 6 Preparation of ethyl 2-amino-4-bromo-1H-imidazole-5-carboxylate

[0126] The compound was prepared according to the method of Example 2.1, but 3-bromoimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester was used instead of 3-fluoroimidazo[1,2-a]pyrimidine-2-carboxylic acid ethyl ester to give 2-amino-4-bromo-1H-imidazole-5-carboxylic acid ethyl ester.

[0127] (ES, m / z): [M-1]=233.98, 235.98.

[0128] Example 7 Preparation of ethyl 4-bromo-1H-imidazole-5-carboxylate

[0129] The compound was prepared according to the method of Example 3.1, except that 2-amino-4-bromo-1H-imidazole-5-carboxylic acid ethyl ester was used instead of 2-amino-4-fluoro-1H-imidazole-5-carboxylic acid ethyl ester to give 4-bromo-1H-imidazole-5-carboxylic acid ethyl ester.

[0130] (ES, m / z): [M-1]=216.97, 218.97.

[0131] Although the present invention has been described in detail above, it will be appreciated by those skilled in the art that various modifications and changes may be made to the present invention without departing from the spirit and scope of the present invention.

Claims

1. A method for preparing a compound of formula IIA, comprising The compound represented by formula III is subjected to a deamination reaction to prepare the compound represented by formula IIA: in, Y is halogen; and R 1 is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10 Substituents of the aryl group substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 Aryl.

2. The method according to claim 1, further comprising The compound represented by formula IV is subjected to a ring-opening reaction to prepare the compound represented by formula III: in, R in Formula IV 1 As defined in claim 1.

3. A method for preparing a compound of formula III, comprising The compound represented by formula IV is subjected to a ring-opening reaction to prepare the compound represented by formula III: in, Y is halogen; and R 1 is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10 Substituents of the aryl group substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 Aryl.

4. The method according to any one of claims 1 to 3, which satisfies one or more of the following: (1) Y is fluorine, fluorine, bromine or iodine, preferably fluorine; (2)R 1 C 1-6 The alkyl group is preferably an ethyl group.

5. The method of claim 1 or 2, wherein the deamination reaction comprises subjecting the compound of formula III to diazotization and reduction of a diazonium salt, satisfying one or more of the following: (1) the diazotization reaction and the reduction reaction of the diazonium salt are carried out by subjecting the compound represented by Formula III to a diazotization reagent in the presence of a reducing agent to carry out a diazotization reaction and a reduction reaction of the diazonium salt; or the diazotization reaction is carried out by subjecting the compound represented by Formula III to a diazotization reagent to carry out a diazotization reaction to generate a diazonium salt, and then carrying out a reduction reaction of the diazonium salt in the presence of a reducing agent; (2) The diazotization reaction and the reduction reaction of the diazonium salt are carried out at a low temperature, preferably not exceeding 10°C, preferably -15 to 10°C, preferably -15 to 5°C. (3) The diazotizing agent is a nitrous acid solution selected from one or more of sodium nitrite, potassium nitrite, isopropyl nitrite, n-butyl nitrite, tert-butyl nitrite, n-amyl nitrite, tert-butyl nitrite, and isoamyl nitrite, preferably sodium nitrite; (4) The reducing agent is selected from an organic reagent or an inorganic reagent, preferably selected from one or more of alcohols, HCHO / NaOH, formic acid, hydroquinone, glucose / NaOH, NaBH4, H3PO2, SnCl2, Na2S2O4, FeSO4, and zinc powder, more preferably H3PO2; (5) Optionally, an acidic solution or an organic solvent is introduced into the reaction system, wherein the acidic solution is selected from one or more of nitric acid, sulfuric acid, hydrochloric acid, phosphoric acid, hypophosphorous acid, formic acid, acetic acid, propionic acid, and hydrobromic acid, preferably one or more of hydrochloric acid, sulfuric acid, phosphoric acid, or hypophosphorous acid, preferably hydrochloric acid or hypophosphorous acid; and the organic solvent is selected from one or more of tetrahydrofuran (THF), acetonitrile (ACN), and 1,4-dioxane; (6) Optionally, a catalyst is added to the reduction reaction of the diazonium salt. Preferably, the catalyst is selected from metal copper compounds, more preferably selected from one or more of cuprous oxide, cuprous chloride, and cupric sulfate.

6. The method according to claim 2 or 3, wherein the ring-opening reaction is carried out in the presence of hydroxylamine hydrochloride / base or hydroxylamine aqueous solution.

7. The method of claim 6, which satisfies one or more of the following: (1) The base is selected from an organic base or an inorganic base, preferably one or more selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), pyridine, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, sodium hydroxide, and potassium hydroxide, more preferably sodium carbonate; (2) the ring-opening reaction is carried out at 20 to 75° C., preferably at 20 to 50° C., preferably at 30 to 40° C., preferably at 35 to 40° C.; (3) the molar ratio of the compound of formula IV to hydroxylamine is 1:1 to 10, preferably 1:2 to 7, preferably 1:3 to 5, preferably about 1:4; (4) The molar ratio of the compound of formula IV to the base is 1:1 to 20, preferably 1:2 to 16, preferably 1:2 to 10; (5) The ring-opening reaction is carried out in an organic solvent, preferably the organic solvent is selected from alcohols, N,N-dimethylacetamide (DMA), and N,N-dimethylformamide (DMF), more preferably N,N-dimethylformamide (DMF).

8. The method according to claim 2 or 3, comprising synthesizing the compound represented by formula IVA using 2-aminopyrimidine as a raw material via the following route: in, R 1 As defined in claim 2 or 3.

9. A compound as shown in formula III', in, Y is halogen; and R 1 is optionally substituted by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 Alkoxy, C 2-7 Alkoxycarbonyl, C 3-6 Cycloalkyl and C 6-10 Substituents of the aryl group substituted with C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or C 6-10 Aryl, M - It is an acid ion, preferably a chloride ion, a bromide ion, a nitrate ion, a nitrite ion, a dihydrogen phosphate ion, a hypophosphite ion, a formate ion, an acetate ion, a propionate ion or a hydrogen sulfate ion, and more preferably a chloride ion, a dihydrogen phosphate ion, a hypophosphite ion or a hydrogen sulfate ion.

10. A compound or a salt thereof as shown below, 11. A method for preparing a compound of formula IA, comprising using the method of any one of claims 1 to 8 or using the compound of claim 9 or 10, Where Y and R 1 As defined in claim 1.

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