WO2022028941A1

WO2022028941A1 - A process for preparation of oxazole compounds

Info

Publication number: WO2022028941A1
Application number: PCT/EP2021/070913
Authority: WO
Inventors: Werner Bonrath; Le DAI; Xixiang DAI; Qiangqiang LIU; Kun Peng; René Tobias STEMMLER; Liuhai WU; Lei Zhang
Original assignee: Dsm Ip Assets B.V.
Priority date: 2020-08-06
Filing date: 2021-07-27
Publication date: 2022-02-10
Also published as: EP4192820A1; CN116075498A

Abstract

The present invention provides a new process for producing an oxazole compound of formula (I), which can avoid toxic and corrosive reagent, and salts by-products and has high efficiency,formula (I). Wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents.

Description

A process for preparation of oxazole compounds

Technical Field

The present invention is related to a new process for producing oxazole compounds.

Background of the Invention

Oxazole compounds represent a vast class of heterocyclic aromatic organic compounds. Oxazole compounds have become increasingly important because of biological activities and their use as intermediates for the preparation of new biological materials. The wide range of biological activities of oxazole compounds includes anti-inflammatory, analgesic, antibacterial, antifungal, hypoglycemic, antiproliferative, anti-tuberculosis, muscle relaxant and HIV inhibitor activity.

4-methyl-5-cyanooxazole is an important intermediate for producing vitamin B₆. In industry, it is mainly produced by the process comprising the steps: a) ethyl acetoacetate is chlorinated to chloroethyl acetoacetate, b) chloroethyl acetoacetate is reacted with formamide to give 4-methyl-5-oxazolecarboxylic acid ethyl ester, and c) the obtained ester is dehydrated to 4-methyl-5-cyanooxazole via 4-methyl-5- oxazole carboxamide. (Werner Bonrath; Kun Peng, Qiong-Mei Zhang, Horst Pauling, Bernd-Jurgen Weimann, Ullmann's Encyclopedia of Industrial Chemistry (7th Edition) (2020)).

The above process has several disadvantages. For example, the chlorination step uses chlorine and the dehydration reaction uses phosphorus pentoxide or acetic anhydride, which are toxic or corrosive. In addition, the process produces many salts which cause environment problem.

Therefore, there is still demand of new processes for producing oxazole compounds.

Summary of the Invention

The present invention provides a new process for producing an oxazole compound of formula (I), which can avoid toxic and corrosive reagents, and reduce salts by-products with high efficiency,

wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents.

The present invention also provides a new intermediate compound of formula (II), which can be used directly to produce the compound of formula (I) in an efficient way,

wherein R is as defined above, and X is halogen.

Detailed Description of the Invention

In the present invention, the term "lower alkyl" as used refers to Ci-Cw alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, the "lower alkyl" is Ci-C₆ alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tertbutyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the "lower alkyl" is methyl or ethyl.

In the present invention, the term "aryl" as used refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.

In the present invention, the term "lower alkoxyl" as used refers to the structure represented by (lower alkyl)-O-, wherein the lower alkyl is as defined above.

In the present invention, the term "halo" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br. In the present invention, the term "salt" or "salts" as used refers to any anionic and cationic complex, such as the complex formed by a cation and an anionic form of the compound of the present invention. Non-limiting examples of the cation include inorganic and organic cations, e.g., cations of the alkali and alkaline earth metals, such as sodium (Na), lithium (Li), potassium (K), calcium (Ca), magnesium (Mg), and the like, as well as ammonium, quaternary ammonium, and amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium and ethylammonium, and the like.

In the present invention, the term "substituent" or "substituents" as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH₂, -NO₂, cyano and/or isocyano.

In the present invention, a compound represented by a formula or a name also cover stereoisomers thereof, including diastereomers and enantiomers, such as cis/trans-isomers or E/Z-isomers.

Particularly, the present invention provides a process for producing a compound of formula (I), comprising the steps: a) Halogenating a compound of formula (III) or a salt thereof to produce a compound of formula (II); and

b) Cyclizing the compound of formula (II) to obtain the compound of formula (I),

wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents; and X is halogen. Preferably, R is H, or lower alkyl optionally substituted by one or more substituents. More preferably, R is H or Ci-C₆ alkyl optionally substituted by one or more substituents. Most preferably, R is H or methyl or ethyl. The most preferably, Ri is H or methyl.

In the present invention, the salt of the compound of formula (III) may be a compound of formula (III') or its tautomeric form of formula (III"):

wherein R is as defined above, and Y is a metal element such as alkali metal elements such as lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs); or alkaline-earth metal elements such as beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba); and iron (ll/lll), nickel (Ni) and cobalt (Co). Preferably, Y is Na or K.

In the step a) of the process of the present invention, the compound of formula (III) or a salt thereof may be halogenated by a halogen or a halogen-containing compound.

In the present invention, the halogen-containing compound may be a halide salt such as alkali metal salts, alkaline-earth metal salts or quaternary ammonium salts of a halogen. Examples of the halide salt include but are not limited to KF, NaF, NaBr, KBr, MgBr₂, NaCI, KCI, RbCI, CuCI₂, LiCI, AgCI, CaCI₂, KI, Agl₂, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzalkonium chloride (BAC), dimethyldioctadecyl-ammonium bromide (DDAB) and dodecyl trimethyl ammonium chloride (DTAC). Preferably, the halide is NaBr and KBr.

In the present invention, the halogen-containing compound may also be a halogen-containing organic compound. Example of the suitable halogen-containing organic compound includes but is not limited to N-Bromosuccinimide (NBS), N-Chlorosuccinimide (NCS), N-lodosuccinimide (NIS), halo hydantoin such as dibromohydantoin, dichlorohydantoin and diiodohydantoin, and halo cyanuric acid such as cyanuric fluoride, trichloroisocyanuric acid, tribromoisocyanuric acid and triiodoisocyanuric acid. In an embodiment of the present invention, the compound of formula (III) or a salt thereof is halogenated by a halogen, preferably in the presence of a base. The base may be any organic or inorganic base or mixture thereof which can neutralize hydrogen halide generated in the reaction. Example of the base includes but is not limited to as KOH, NaOH, Na₂CO₃, K₂CO₃, NaNH₂, KF/AI₂O₃, potassium tert-butoxide (t- BuOK), sodium t-pentyloxide and the others. Preferably, the base is K₂CO₃. The halogen may be added into the reaction in an amount of from 0.1 mol to 2 mol, preferably from 0.2 mol to 1.5 mol, more preferably from 0.3 mol to 1 mol, such as 0.3, 0.35, 0.4, 0.45. 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95 and 1 mol, per 1 mol of the compound of formula (III). The base may be added into the reaction in an amount of from 0.1 mol to 10 mol, preferably from 0.5 mol to 8 mol, more preferably from 1.0 mol to 5 mol, such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 and 5 mol, per 1 mol of the compound of formula (III).

In a preferable embodiment of the present invention, the compound of formula (III) or a salt thereof is halogenated by a halide salt as defined above in the presence of an oxidant. The oxidant may be any oxidant known in the art. A good example of the oxidant includes but is not limited to peroxides such as hydrogen peroxide, peroxyformic acid, peroxyacetic acid, peroxypropionic acid, peroxide benzenesulfonyl acid, peroxide p-toluenesulfonyl acid and peroxide methylsulfonyl acid. The halide salt may be added into the reaction in an amount of from 0.5 mol to 5.0 mol, preferably from 0.8 mol to 3.0 mol, more preferably from 1.0 mol to 2.0 mol, such as 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2.0 mol, per 1 mol of the compound of formula (III). The oxidant may be added into the reaction in an amount of from 1 mol to 10 mol, preferably from 2 mol to 8 mol, more preferably from 0.5 mol to 5 mol, preferably from 1.0 mol to 4.0 mol, more preferably from 1.5 mol to 3.0 mol, such as 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 and 3.0 mol, per 1 mol of the compound of formula (III).

In the embodiment that the compound of formula (III) or a salt thereof is halogenated by a halide salt, the halogenation is preferably carried out in the presence of an acid. The acid may be any organic acid such as aliphatic acid or aromatic acid, or inorganic acid. Examples of the organic acid include but are not limited to lactic acid, acetic acid, formic acid, propanoic acid, butanoic acid, benzoic acid, p-methyl benzoic acid, citric acid, oxalic acid, malic acid and tartaric acid. Examples of the inorganic acid include but are not limited to hydrochloric acid (HCI), nitric acid (HNO₃), phosphoric acid (H₃PO₄), sulfuric acid (H₂SO₄), sulfurous acid (H₂SO₃), carbonic acid (H₂CO₃), hydrofluoric acid (HF) and hydrobromic acid (HBr). Preferably, the acid is organic acid. More preferably, the acid is formic acid, acetic acid, benzoic acid or 4- methylbenzoic acid. The acid may be added into the reaction in an amount of from 0.1 mol to 10 mol, preferably from 0.5 mol to 8.0 mol, more preferably from 1 mol to 5 mol, such as 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 and 5.0 mol, per 1 mol of the compound of formula (III). In such an embodiment, a pH modifier such as sodium dihydrogen phosphate (NaH₂PO₄) and disodium hydrogen phosphate (Na₂HPO₄) may be added to maintain the pH value of the reaction mixture at from 3.5 to 6.0, preferably from 4.0 to 5.5.

In a more preferable embodiment, the compound of formula (III) or a salt thereof is halogenated by a halogen-containing organic compound such as N-Bromosuccinimide (NBS), N-Chlorosuccinimide (NCS), N- lodosuccinimide (NIS), dibromohydantoin, dichlorohydantoin, diiodohydantoin, cyanuric fluoride, trichloroisocyanuric acid, tribromoisocyanuric acid and triiodoisocyanuric acid. The halogen-containing organic compound may be added into the reaction in an amount of from 0.1 mol to 5 mol, preferablyfrom 0.2 mol to 3 mol, more preferably from 0.3 mol to 2 mol, such as 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2 mol, per 1 mol of the compound of formula (III).

In the step a) of the process of the present invention, one or more solvents may be used. Examples of the suitable solvents include but are not limited to esters such as ethyl acetate, propyl acetate and butyl acetate, alcohols such as methanol and ethanol, nitriles such as acetonitrile (ACN) and benzonitrile, and benzene, toluene, chlorobenzene, xylene, dimethylformamide (DMF), dichloromethane (DCM), water and others that are common-used as a solvent in the field. Preferably water or butyl acetate or DCM is used as the solvent. More preferably two or more solvents which are immiscible are used. The most preferably, water and butyl acetate or DCM are used as the solvents.

In the step a) of the process of the present invention, the solvents may be added into the reaction in an amount of from 0.1 L to 20 L, preferably from 0.2 Lto 15 L, more preferably from 0.5 L to 10 L, such as 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 L, per 1 mol of the compound of formula (III).

In the step a) of the process of the present invention, a catalyst may be used. The catalyst may be any metal catalyst. Examples of the suitable catalyst include but are not limited to Cu(OAc)₂, CuCI₂, FeCI₃, CoCI₂, NH4VO3, Na₂WO₄, and heteropoly acid such as phosphotungstic acid, silicoptungstigacid (H₄PWI₂O₄₀ (hydrate) and phosphomolybdic acid, and hydrate thereof. More preferably, the catalyst is Cu(OAc)₂, Na₂WO₄»2H₂O, FeCI₃»6H₂O, CoCI₂, CuCI₂»2H₂O and phosphotungstic acid hydrate. The catalyst may be added into the reaction in an amount of from 0.0001 mol to 0.5 mol, preferably from 0.0005 mol to 0.4 mol, more preferably from 0.001 mol to 0.3 mol, such as 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25 and 0.3 mol, per 1 mol of the compound of formula (III).

In the process of the present invention, the halogenation of the step a) may be carried out at room temperature. The obtained compound of formula (III) may be directly used for the next step or easily isolated by any known process, such as evaporation, extraction and/or crystallization, for use in the next step.

In the step b) of the process of the present invention, the cyclization may be achieved by treating the compound of formula (II) with one or more bases. The suitable bases may be strong bases, including but not limited to organic base such as l,5-diazabicyclo(4.3.0)non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), and alkoxide such as potassium tert-butoxide (tBuOK) and sodium t-pentyloxide; and inorganic base such as NaH, KOH, NaOH, Na₂CO₃, K₂CO₃, KF/AI₂O₃, Cs₂CO₃ and NaNH₂, and mixture thereof. Preferably the base is NaH, DBN, DBU, TMG, Cs₂CO₃, NaNH₂, or K₂CO₃, or mixture thereof. The amount of the bases used in the step may be from 0.1 mol to 10 mol, preferably from 0.5 mol to 8 mol, more preferably from 1 mole to 5 moles such as 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 and 10 moles, per 1 mole of the compound of formula (II).

In the step b) of the process of the present invention, one or more solvents are preferably used. Examples of the solvents suitable for the step b) of the process include but are not limited to alcohol such as n- butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), 2-methyl tetrahydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC) and propylene carbonate (PC); ketone such as cyclohexanone, diisopropylketone and Cyrene™; aprotic dipolar solvents such as DMF, dimethylacetamide (DMAc), N,N-dimethylbenzamide (DMBA), ACN, benzonitrile, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) and dibutylformamide (DBF); halide solvents such as dichloroethane (DCE), DCM and chloroform; organic bases such as pyridine and quinoline; deep eutectic solvent such as choline chloride (ChCI)/urea, AcChCl/urea and ZnCI₂/urea; and ionic liquid such as l-ethyl-3-methylimidazolium tetrafluoroborate ([emim[[BF₄]), l-butyl-3- methylimidazolium chloride ([bmim][CI]) and 1-butylpyridinium chloride ([bpy][CI]). Preferably the solvent is acetonitrile, DMAc, PC, pyridine and/or DMF. The amount of the solvent used in the step may be from 0.1 L to 50 L, preferably from 0.5 L to 30 L, more preferably from 1 L to 20 mL, such as 1, 2, 3, 4,

5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 L, per 1 mol of the compound of formula (II).

In the step b) of the process of the present invention, a catalyst may be used or not. The catalyst may be any metal catalyst, preferably any Lewis acid salt, for example, those formed by metal element of Group IB, IIB and VIIIB in the Periodic Table of Elements such as element silver (Ag), cobalt (Co), copper (Cu), iron (Fe), indium (In), lanthanum (La), manganese (Mn), nickel (Ni), platinum (Pt), palladium (Pd), rhodium (Rh) and zinc (Zn); or any quaternary ammonium salt catalyst such as tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzalkonium chloride (BAC), dimethyldioctadecyl-ammonium bromide (DDAB) and dodecyl trimethyl ammonium chloride (DTAC). Examples of the catalyst include but are not limited to Ag₂CO₃, silver acetate (AgOAc), silver triflate (AgOTf), silver tungstate (Ag₂WO₄), cobalt(ll) acetylacetonate (Co(acac)₂), Co(OAc)₂, Cu(acac)₂, Cu(OAc)₂, Cu(OTf)₂, Fe(acac)₂, Fe(OTf)₃, Pd(OAc)₂, PtCI₂, Zn(OTf)₂, ZnCI₂, and Zn(OAc)₂. The catalyst may be added into the reaction in an amount of from 0.01 mol to 0.5 mol, preferably from 0.02 mol to 0.4 mol, more preferably from 0.03 mol to 0.2 mol, such as 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.2 mol, per 1 mol of the compound of formula (III).

In the step b) of the process of the present invention, the cyclization may be carried out at the temperature from 10°C to 200°C, preferably from 20°C to 180°C, more preferably from 50°C to 150°C such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 and 150°C. Preferably, the cyclization is carried out at from 80°C to 120°C such as 80, 85, 90, 95, 100, 105, 110, 115 and 120°C.

The obtained compound of formula (I) may be easily isolated by any known process, such as extraction and/or crystallization.

The compound of formula (III) as raw material can be synthesized by known process or according to the processes as disclosed in the examples of the present invention.

The present invention hereby provides a simple process for producing oxazole compounds, which saves steps, avoids salts by-products and provides high yield. Surprisingly, the inventors of the present invention discovered that the intermediate compound of formula (II) is new. Accordingly, the present invention also provides a new intermediate compound of formula (II):

Wherein R and X are as defined above.

Preferably, R is H, or lower alkyl optionally substituted by one or more substituents. More preferably, R is H or Ci-C₆ alkyl optionally substituted by one or more substituents. More preferably, R is H or methyl or ethyl. The most preferably, Ri is H or methyl.

The compound of formula (II) can be converted to the oxazole compound of formula (I) directly in an efficient way with high yield.

The present invention will be further illustrated by the following examples.

Examples

Example 1

A dried four necked round bottom flask was charged with liquid ammonia (50 mL, 2.05 mol, 16 eq). After the flask was flushed with argon, iron nitrate nonahydrate (35 mg, 0.087 mmol, 0.00067 eq) was added. Then sodium (2.96 g, 129 mmol, 1.0 eq) was added and stirred for 30 mins at -40°C to -50°C. At the same temperature anhydrous acetonitrile (11.65 g, 283 mmol, 2.2 eq) was added dropwise in 15 mins and anhydrous toluene (40 mL) was added immediately. The reaction mixture was warmed to room temperature in 1 hour and stirred for additional 1 hour to obtain a grey suspension. Ethyl formate (10.71 g, 142 mmol, 1.1 eq) dissolved in anhydrous toluene (20 mL) was added dropwise in 20 mins. The reaction mixture was stirred overnight to obtain a grey and thick suspension. TBME (100 mL) was added and the mixture was filtrated over a paper filter (7 cm diameter) to obtain a filter cake.

The filter cake was loaded in a four necked round bottom flask under argon atmosphere. Butyl acetate (100 mL) was added and acetic acid (7.75 g, 129 mmol, 1.0 eq) was added dropwise in 5 mins. The reaction mixture was stirred for 30 mins at room temperature and then filtered over a paper filter (7 cm diameter). The filtrate was dried at 45°C (2 mbar) to produce a colorless oil which crystallized slowly to obtain the compound 1 (13.22 g, 98.8wt% purity, 92% yield).

²H NMR of Z-isomer of compound 4 (400 MHz, DMSO) 6 (ppm): 10.20 (1H), 8.43 (1H), 4.90 (1H), 2.15 (3H). ²H NMR of £-isomer of compound 4 (400 MHz, DMSO) 6 (ppm): 10.40 (1H), 8.81 - 8.14 (1H), 6.37 - 4.78 (1H), 2.39 -1.97 (3H).

Example 2

To a suspension of compound 1 (227 mg, 2.0 mmol), NaBr (249.6 mg, 2.86 mmol), Cu(OAc)z (22 mg, 0.12 mmol) and acetic acid (240 mg, 4.0 mmol) in DCM (1 mL), an aqueous solution of hydrogen peroxide (600 mg, 28% w/w, 4.94 mmol) was added dropwise in 2 hours and the reaction mixture was stirred for another 10 hours at room temperature. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was analyzed by HPLC to give 354.5 mg compound 2 with 93.8% yield.

Example 3

To a suspension of the compound 1 (227 mg, 2.0 mmol), NaBr (312 mg, 3.0 mmol), Na₂WO₄»2H₂O (2.2 mg, 0.006 mmol) and acetic acid (240 mg, 4.0 mmol) in n-butyl acetate (1.5 mL) and H₂O (0.9 mL), an aqueous solution of hydrogen peroxide (600 mg, 17% w/w, 3.0 mmol) was added dropwise in 2 hours and the reaction mixture was stirred for another 6 hours at room temperature. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by HPLC to give 359.1 mg compound 2 with 95.0 % yield.

Example 4

To a suspension of the compound 1 (113 mg, 1.0 mmol), NaBr (156 mg, 1.5 mmol), Na₂WO₄»2H₂O (1.1 mg, 0.003 mmol) and p-methylbenzic acid (272 mg, 2.0 mmol) in n-butyl acetate (1.5 mL) and H₂O (0.9 mL), an aqueous solution of hydrogen peroxide (300 mg, 17% w/w, 1.5 mmol) was added dropwise in 2 hours and the reaction mixture was stirred for another 6 hours at room temperature. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by HPLC to give 109.8 mg compound 2 with 58.1 % yield.

Example 5

To a suspension of the compound 1 (12.25 g, 0.1 mol), NaBr (15.6 g, 1.5 mol) and Na₂WO4»2H₂O (0.11 g, 0.3 mmol) in n-butyl acetate (75 mL) and H₂O (32.0 mL), an aqueous solution of hydrogen peroxide (17.0 g, 30% w/w, 0.15 mol) was added dropwise in 4 hours at 25°C and CO₂ was bubbled into aqueous phase at the same time. The reaction mixture was hold for another 2 hours. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by HPLC to give compound 2 with 75 % yield.

Example 6

To a suspension of the compound 1 (12.25 g, 0.1 mol), NaBr (7.8 g, 0.075 mol), Na₂WO₄»2H₂O (0.11 g, 0.3 mmol) and NaH₂PO₄ (12.0 g, 0.1 mol) in n-butyl acetate (75 mL) and H₂O (32.0 mL), an aqueous solution of hydrogen peroxide (17.0 g, 30% w/w, 0.15 mol) and aqueous HBr (16.88 g, 0.10 mol) were added simultaneously dropwise in 4 hours at 25°C. The reaction mixture was hold for another 1 hour. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by HPLC to give compound 2 with 89.8 % yield.

Example 7

To a suspension of the compound 1 (227 mg, 2.0 mmol), NaBr (249.6 mg, 2.86 mmol), phosphotungstic acid hydrate (10 mg, 0.002 mmol) and acetic acid (240 mg, 4.0 mmol) in H₂O (5.4 mL), an aqueous solution of hydrogen peroxide (600 mg, 17% w/w, 3.0 mmol) was added dropwise in 2 hours and the reaction mixture was stirred for another 12 hours at room temperature. The reaction mixture was extracted by ethyl acetate (3x6 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was analyzed by HPLC to give 372.7 mg compound 2 with 98.6 % yield.

Example 8

To a suspension of the compound 1 (227 mg, 2.0 mmol), KBr (357 mg, 3.0 mmol), Na₂WO₄.2H₂O (2.2 mg, 0.006 mmol) and acetic acid (240 mg, 4.0 mmol) in n-butyl acetate (1.5 mL) and H₂O (0.9 mL) was added dropwise an aqueous solution of hydrogen peroxide (600 mg, 17% w/w, 3.0 mmol) in water in 2 hours and hold for another 6 hours at room temperature. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by HPLC to give the compound 2 (360.2 mg, 95.3 % yield)

Example 9

To a suspension of the compound 1 (227 mg, 2.0 mmol) and K₂CO₃ (552 mg, 4 mmol) in DMF (3 mL), Br₂ (178 mg, 1.11 mmol) in DMF (1 mL) was added in 30 minutes at room temperature and the reaction mixture was stirred for one hour at the same temperature. The mixture was filtered off and the filtrate was analyzed by HPLC to give compound 2 (273 mg, 70.1% yield).

Example 10

2

To a suspension of the compound 1 (2.27 g, 20.0 mmol) in DMF (50 mL) was added NBS (2.19 g, 24.6 mmol) in 4 portions in 30 minutes at room temperature and hold for another 2 hours. The reaction solution was washed with 20.0 g water, organic phase was analyzed by HPLC to give the compound 2 (3.60 g, 95.1 % yield). Example 11

Dibromohydantoin

To a suspension of the compound 1 (56.0 mg, 0.5 mmol) in DCM (1 mL) was added dibromohydantoin (86 g, 0.3 mmol) at room temperature and hold for 10 minutes. DCM (5 mL) and H₂O (3 mL) were added to the reaction mixture and stirred for another 10 minutes. After separation, the organic phase was analyzed by HPLC to give the compound 2 (90.6 mg, 95.9% yield).

Example 12

Trichloroisocyanuric acid 4

To a suspension of the compound 1 (2.27 g 20.0 mmol) in DCM (50 mL) was added trichloroisocyanuric acid (2.37 g, 10.0 mmol) in 3 portions in 30 minutes at room temperature and hold for another 2 hours, the reaction solution was washed with 20.0 g water. Organic phase was analyzed by HPLC to give the compound 4 (2.20 g, 75.4 % yield).

Example 13

To a suspension of the compound 1 (227 mg, 2.0 mmol), NaBr (312 mg, 3.0 mmol), the catalysts as listed in below table and acetic acid (240 mg, 4.0 mmol) in n-butyl acetate (1.5 mL) and H₂O (0.9 mL), an aqueous solution of hydrogen peroxide (600 mg, 17% w/w, 3.0 mmol) was added dropwise in 2 hours and the reaction mixture was stirred for another 6 hours at room temperature. The organic phase was collected, and the aqueous phase was extracted with n-butyl acetate. The combined organic phase was analyzed by

HPLC to give compound 2.

Example 14

Under N₂ atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) in ACN (10 mL), DBU (387 uL, 2.60 mmol) was added. The reaction mixture was stirred at 70°C for two hours. After reaction completed, the solvent was removed by rotational evaporation. The yield of compound 3 was determined by quantitative HPLC (95 mg, 87% yield).

Example 15

Under N₂ atmosphere, to a solution of compound 2 (380 mg, 2.00 mmol) in ACN (2 mL), DBN (372 mg, 3.0 mmol) was added. The reaction mixture was stirred at 80°C for 30 mins. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (36 mg, 33% yield). Example 16

Under N2 atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) in DMF (10 mL), DBU (387 uL, 2.60 mmol) was added. The reaction mixture was stirred at 70°C for two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (93 mg, 86% yield).

Example 17

Under N₂ atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) in pyridine (10 mL), DBU (387 uL, 2.60 mmol) was added. The reaction mixture was stirred at 70°C for two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (82 mg, 75% yield).

Example 18

Under N₂ atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) in PC (10 mL), DBU (387 uL, 2.60 mmol) was added. The reaction mixture was stirred at 80°C for two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (84 mg, 77% yield). Example 19

Under N₂ atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) in DMAc (10 mL), TMG (288 mg, 2.5 mmol) was added. The reaction mixture was stirred at 75°C for two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (87 mg, 80% yield).

Example 20

Under N₂ atmosphere, compound 2 (191 mg, 1.01 mmol) and K₂CO₃ (621 mg, 4.50 mmol) were dissolved in DMAc (2 mL). The reaction mixture was stirred at 90°C for four hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (76 mg, 70% yield).

Example 21

Under N₂ atmosphere, compound 2 (191 mg, 1.01 mmol) and Cs₂CO₃ (488 mg, 1.50 mmol) were dissolved in DMAc (5 mL). The reaction mixture was stirred at 90°C for three hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (65 mg, 60% yield).

Example 22

Under N₂ atmosphere, compound 2 (191 mg, 1.01 mmol) and NaNH₂ (55 mg, 1.38 mmol) were dissolved in DMAc (10 mL). The reaction mixture was stirred at 70°C for four hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (78 mg, 72% yield).

Example 23

Under N₂ atmosphere, to a solution of compound 2 (191 mg, 1.01 mmol) and zinc triflate (38 mg, 0.1 mmol) in ACN (10 mL), DBU (387 ul, 2.60 mmol) was added. The reaction mixture was stirred at 70°C for two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (101 mg, 93% yield).

Example 24

Under N₂ atmosphere, compound 2 (191 mg, 1.01 mmol), silver triflate (13 mg, 0.05 mmol) and Cs₂CO₃ (488 mg, 1.50 mmol) were dissolved in DMAc (5 mL). The reaction mixture was stirred at 90°C for three hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (83 mg, 77% yield).

Example 25

Under N2 atmosphere, to a solution of DBU (11.0 ml, 72.2 mmol) and zinc acetate (0.27 g, 1.48 mmol) in ACN (25 mL), compound 2 (9.10 g, 48.1 mmol) dissolved in ACN (25 mL) was dosed in 2 hours. The reaction mixture was stirred at 90°C in oil bath during dosing and hold for additional two hours. After reaction completed, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (4.72 g, 91% yield).

Example 26

Under N₂ atmosphere, NaH (80mg, 60%, 2.0 mmol) was add to a solution of compound 2 (387 mg 2.0 mmol) in DMF (2 mL) and stirred at room temperature for 5 minutes, then DBU (60.8 mg, 0.4 mmol) was added and stirred at 100°C for another 5 minutes, the reaction mixture was cooled to room temperature. The yield of compound 3 was determined by quantitative HPLC (173 mg, 80 % yield).

Claims

1. A process for producing a compound of formula (I), comprising the steps: a) Halogenating a compound of formula (III) or a salt thereof to produce a compound of formula (II); and

wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents; and X is halogen.

2. The process of claim 1, wherein R is H or Ci-C₆ alkyl optionally substituted by one or more substituents.

3. The process of claim 1, wherein R is H or methyl or ethyl.

4. The process of claim 1, wherein the salt of the compound of formula (III) is a compound of formula (III') or its tautomeric form of formula (III"):

(HI’) (HI") wherein R is defined as claims 1-3, and Y is a metal element such as alkali metal elements such as lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs); or alkaline-earth metal elements such as beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba); and iron (ll/lll), nickel (Ni) and cobalt (Co).

5. The process of any one of claims 1-4, wherein, in the step a), the compound of formula (III) or a salt thereof is halogenated by a halogen or a halogen-containing compound.

6. The process of claim 5, wherein the halogen-containing compound is a halide salt such as alkali metal salts, alkaline-earth metal salts or quaternary ammonium salt of a halogen, including but not limited to KF, NaF, NaBr, KBr, MgBr₂, NaCI, KCI, RbCI, CuCI₂, LiCI, AgCI, CaCI₂, KI, Agl₂, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), benzalkonium chloride (BAC), dimethyldioctadecyl-ammonium bromide (DDAB), dodecyl trimethyl ammonium chloride (DTAC).

7. The process of claim 5, wherein the halogen-containing compound is a halogen-containing organic compound, including but not limited to N-Bromosuccinimide (NBS), N-Chlorosuccinimide (NCS), N- lodosuccinimide (N IS), halo hydantoin such as dibromohydantoin, dichlorohydantoin and diiodohydantoin, and halo cyanuric acid such as cyanuric fluoride, trichloroisocyanuric acid, tribromoisocyanuric acid and triiodoisocyanuric acid.

8. The process of any one of claims 1-4, wherein the compound of formula (III) or a salt thereof is halogenated by a halogen in the presence of a base.

9. The process of claim 8, wherein the base is any organic or inorganic base selected from the group consisting of KOH, NaOH, Na₂CO₃, K₂CO₃, NaNH₂, KF/AI₂O₃, potassium tert-butoxide (t-BuOK) and sodium t-pentyloxide, or mixture thereof.

10. The process of any one of claims 1-4, wherein the compound of formula (III) or a salt thereof is halogenated by a halide salt in the presence of an oxidant.

11. The process of claim 10, wherein the oxidant is selected from the group consisting of hydrogen peroxide, peroxyformic acid, peroxyacetic acid, peroxypropionic acid, peroxide benzenesulfonyl acid, peroxide p-toluenesulfonyl acid and peroxide methylsulfonyl acid.

12. The process of claim 10, wherein the halogenation is carried out in the presence of an acid.

13. The process of claim 13, wherein the acid is any organic acid such as aliphatic acid or aromatic acid, including but not limited to lactic acid, acetic acid, formic acid, propanoic acid, butanoic acid, benzoic acid, 4-methylbenzoic acid, citric acid, oxalic acid, malic acid and tartaric acid; or any inorganic acid, including but not limited to hydrochloric acid (HCI), nitric acid (HNO₃), phosphoric acid (H₃PO₄), sulfuric acid (H2SO4), sulfurous acid (H₂SO₃), carbonic acid (H₂CO₃), hydrofluoric acid (HF) and hydrobromic acid (HBr).

14. The process of any one of claims 1-13, wherein one or more solvents are used in the step a).

15. The process of claim 14, wherein the solvents are selected from the group consisting of esters such as ethyl acetate, propyl acetate and butyl acetate, alcohols such as methanol and ethanol, nitriles such as acetonitrile (ACN) and benzonitrile, and benzene, toluene, chlorobenzene, xylene, dimethylformamide (DMF), dichloromethane (DCM), and water.

16. The process of claim 14, wherein two or more solvents such as DCM and water are used.

17. The process of any one of claims 1-16, wherein a catalyst is used in the step a).

18. The process of any one of claims 17, wherein the catalyst is any metal catalyst including but not limited to Cu(OAc)₂, CuCI₂, FeCI₃, CoCI₂, NH₄VO₃, Na₂WO₄, and heteropoly acid such as phosphotungstic acid, silicoptungstigacid (H₄RWI₂O₄₀ (hydrate) and phosphomolybdic acid, and hydrate thereof, preferably is FeCI₃»6H₂O, CoCI₂, CuCI₂»2H₂O or phosphotungstic acid hydrate.

19. The process of any one of claims 1-18, wherein, in the step b), the cyclization is achieved by treating the compound of formula (II) with one or more bases.

20. The process of claim 19, wherein the bases are strong bases, including but not limited to organic base such as l,5-diazabicyclo(4.3.0)non-5-ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1, 1,3,3- tetramethylguanidine (TMG), and alkoxide such as potassium tert-butoxide (tBuOK) and sodium t- pentyloxide; and inorganic base such as NaH, KOH, NaOH, Na₂CO₃, K₂CO₃ and NaNH₂, and mixture thereof.

21. The process of any one of claims 1-18, wherein one or more solvents are used in the step b).

22. The process of claim 21, wherein the solvents are selected from the group consisting of alcohol such as n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), 2-methyl tetrahydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC) and propylene carbonate (PC); ketone such as cyclohexanone, diisopropylketone and Cyrene™; aprotic dipolar solvents such as DMF, dimethylacetamide (DMAc), N,N-dimethylbenzamide (DMBA), ACN, benzonitrile, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP) and dibutylformamide (DBF); halide solvents such as dichloroethane (DCE), DCM, chloroform; organic bases such as pyridine and quinoline; deep eutectic solvent such as ChCl/urea, AcChCl/urea and ZnCI₂/urea; and ionic liquid such as [emim[[BF₄], [bmim][CI] and [bpy][CI].

23. The process of any one of claims 1-18, wherein a catalyst is used in the step b).

24. The process of claim 23, wherein the catalyst is any metal catalyst, preferably any Lewis acid salt, for example, those formed by metal element of Group IB, 11 B and VI I IB in the Periodic Table of Elements such as element Silver, Cobalt, Copper, Iron, Indium, Lanthanum, Manganese, Nickel, Platinum, Palladium, Rhodium or Zinc, including but not limited to Ag₂CO₃, Silver acetate, Silver triflate, silver tungstate, Cobalt(ll) acetylacetonate, Co(OAc)₂, Cu(acac)₂, Cu(OAc)₂, Cu(OTf)₂, Fe(acac)₂, Fe(OTf)₃, Pd(OAc)₂, PtCI₂, Zn(OTf)₂, ZnCI₂ and Zn(OAc)₂.

25. The process of any one of the above claims, wherein the cyclization in the step b) is carried out at the temperature from 10°C to 200°C, preferably from 20°C to 180°C, more preferably from 50°C to 150°C such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 and 150°C.

26. A compound of formula (II):