EP4408828A1 - A process for preparation of oxazole compounds - Google Patents

A process for preparation of oxazole compounds

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Publication number
EP4408828A1
EP4408828A1 EP22786301.6A EP22786301A EP4408828A1 EP 4408828 A1 EP4408828 A1 EP 4408828A1 EP 22786301 A EP22786301 A EP 22786301A EP 4408828 A1 EP4408828 A1 EP 4408828A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
chloride
methyl
urea
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP22786301.6A
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German (de)
French (fr)
Inventor
Le DAI
Xixiang DAI
Liuhai WU
Qi Gu
Kun Peng
Werner Bonrath
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DSM IP Assets BV
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DSM IP Assets BV
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Publication of EP4408828A1 publication Critical patent/EP4408828A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention is related to a new process for producing oxazole compounds.
  • 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 B 6 .
  • 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, (see H. Pauling, B.
  • the chlorination step uses chlorine and the dehydration reaction uses phosphorus pentoxide or acetic anhydride, which are toxic or corrosive.
  • the process produces many salts which cause environment problem.
  • the present invention provides a process for producing an oxazole compound of formula (I),
  • R is H, or lower alkyl or aryl optionally substituted by one or more substituents.
  • the process according to the present invention is simple and efficient, and uses less expensive reagents and thus saves cost. Especially the side-products of the process are recyclable.
  • 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.
  • the "lower alkyl” is Ci-C 6 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, cyclonony
  • aryl refers to aromatic hydrocarbon such as phenyl, benzyl, xylyl and naphthalenyl.
  • lower alkoxyl refers to the structure represented by (lower alkyl)-O-, wherein the lower alkyl is as defined above.
  • 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.
  • substituteduent or “substituents” as used refers to lower alkyl, lower alkoxyl, hydroxyl, halo, -NH 2 , -NO 2 , cyano and/or isocyano.
  • 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.
  • the present invention provides a process for producing an oxazole compound of formula (I), comprising the steps: a) Reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV); and b) cyclizing the compound of formula (IV) 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.
  • the compound of formula (III) may be a compound of formula (III').
  • R is as defined above
  • Y is a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH 4 ) or substituted ammonium.
  • Y is Na or K.
  • the compound of formula (IV) may be a compound of formula (IV'):
  • R, X and Y are as defined above.
  • R is H, or lower alkyl optionally substituted by one or more substituents. More preferably, R is H or Ci-C 6 alkyl optionally substituted by one or more substituents. The most preferably, R is H or methyl or ethyl.
  • the compound of formula (III) may be used in an amount of from 0.05 mol to 5 mol, preferably from 0.08 mol to 3 mol, more preferably from 0.1 mol to 2 mol, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8 or 2.0 mol, per 1 mol of the compound of formula (II).
  • one or more solvents may be used.
  • suitable solvents include but are not limited to cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), 2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y- butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and CyreneTM; aprotic dipolar solvents such as dimethylformamide (DMF), acetane, methylformamide (DMF), ace
  • the solvent is butyl acetate, acetonitrile, 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).
  • the reaction may be carried out at the temperature of from 0°C to 50°C, preferably from 10°C to 25°C, more preferably at room temperature.
  • the obtained compound of formula (IV) may be directly used for the next step b) without any treatment, or be isolated by any known process, such as filtration, extraction and/or crystallization, for use in the next step b).
  • the compound of formula (IV) is cyclized to provide the oxazole compound of formula (I).
  • the cyclization may be achieved by heating the compound of formula (IV).
  • the compound of formula (IV) is heated to the temperature of from 30°C to 200°C, more preferably from 40°C to 180°C, the most preferably from 50°C to 150°C such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 and 150°C.
  • the cyclization may be carried out in a solvent.
  • Any solvent that can dissolve the compound of formula (IV) should be suitable.
  • the suitable solvent includes but is not limited to cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME),2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y-butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and CyreneTM; apro
  • the solvent is DMF, NMP, PC, tetramethylurea, l,3-dimethyl-2-imidazodinone, ACN, sulfolane, triethyl phosphate, y-Butyrolactone and/or N- formylmorpholine.
  • the amount of the solvent used in the cyclization 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 (IV).
  • the cyclization in the step b) of the process of the present invention is carried out in the presence of one or more bases.
  • the suitable bases may be selected from alkoxide base such as potassium tert-butoxide (tBuOK), sodium tert-butoxide (tBuONa) and sodium t-pentyloxide (t-pentaONa); other 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), tetramethylguanidine, l,5,7-Triazabicyclo[4,4,0]dec-5-ene (TBD); and inorganic base such as NaH, CaO, KOH, NaOH, Na 2 CO 3 , K 2 CO 3 , KF/AI 2 O 3 , Cs 2 CO 3 and NaNH 2 ; and the mixture thereof.
  • alkoxide base such as potassium tert-butoxide (tBuOK), sodium tert-butoxid
  • the base is DBN, DBU, TMG, TBD, NaH, tBuONa, t-pentaONa, CaO, Na 2 CO 3 , K 2 CO 3 , KF/AI 2 O 3 , CS 2 CO 3 and NaNH 2 , and mixture thereof.
  • the amount of the bases used in the cyclization may be from 0.01 mol to 1 mol, preferably from 0.05 mol to 0.8 mol, more preferably from 0.1 moles to 0.6 moles such as 0.1, 0.2, 0.3, 0.4, 0.5 or 0.6 mole, per 1 mole of the compound of formula (IV).
  • the cyclization in the process of the present invention may be carried out in the absence of a catalyst.
  • a catalyst may be used to accelerate the cyclization reaction.
  • the catalyst suitable for the cyclization in process of the present invention may be 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 (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), dimethyldioctade
  • the catalyst examples include but are not limited toAg 2 CO 3 , silver acetate (AgOAc), silver triflate (AgOTf), silver tungstate (Ag 2 WO 4 ), 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 , PtCI 2 , Zn(OTf) 2 , ZnCI 2 , 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 (IV).
  • the obtained oxazole compound of formula (I) may be easily isolated by any known process, such as extraction and/or crystallization.
  • the obtained side-products in the solvent can be easily recycled.
  • the step a) and the step b) of the process may be carried out in one-pot. Accordingly, the present invention also provides a one-pot process for producing the compound of formula (I) which comprises the step a) and the step b) as described above.
  • the present invention hereby provides a simple process for producing oxazole compounds, which saves steps and cost, avoids salts by-products, and provides high yield.
  • the produced side-products can be recycled and further saves the cost of the process.
  • the filter cake obtained according to Example 1 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 2 (13.22 g, 98.8wt% purity).
  • compound 3 (9.59 g, 50 mmol, 98.5%) was dissolved in DMF (50 ml) in a 100 ml round-bottom flask, and then compound 1 (10.92g, 75 mmol, 95%) was added in one portion.
  • the reaction mixture was stirred at 80°C for 1 h and then cooled down to room temperature to obtain the compound 5 in solution (64% yield by HPLC).

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  • Chemical & Material Sciences (AREA)
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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention provides a process for producing an oxazole compound of formula (I), wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents. The process according to the present invention is simple and efficient, and uses less expensive reagents and thus saves cost. Especially the side-products of the process are recyclable.

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, (see H. Pauling, B. Weimann, Ullmann, VCH, (2012) 248; 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 process for producing an oxazole compound of formula (I),
Wherein R is H, or lower alkyl or aryl optionally substituted by one or more substituents.
The process according to the present invention is simple and efficient, and uses less expensive reagents and thus saves cost. Especially the side-products of the process are recyclable.
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 "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. The present invention provides a process for producing an oxazole compound of formula (I), comprising the steps: a) Reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV); and b) cyclizing the compound of formula (IV) 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.
In the present invention, the compound of formula (III) may be a compound of formula (III'). wherein R is as defined above, and Y is a metal element such as alkali metal elements (lithium (Li), sodium (Na), potassium (K), and cesium (Cs)), or alkaline-earth metal elements (beryllium (Be), magnesium (Mg), calcium (Ca), and barium (Ba)), or Iron (ll/lll); or ammonium (NH4) or substituted ammonium. Preferably, Y is Na or K.
Correspondingly, the compound of formula (IV) may be a compound of formula (IV'):
Wherein R, X and Y 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. The most preferably, R is H or methyl or ethyl.
In the step a) of the process of the present invention, the compound of formula (III) may be used in an amount of from 0.05 mol to 5 mol, preferably from 0.08 mol to 3 mol, more preferably from 0.1 mol to 2 mol, such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8 or 2.0 mol, per 1 mol of the compound of formula (II).
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 cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), 2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y- butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and Cyrene™; aprotic dipolar solvents such as dimethylformamide (DMF), acetonitrile (ACN) and benzonitrile; halide solvents such as dichloroethane (DCE), dichloromethane (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]), 1-butyl- 3-methylimidazolium chloride ([bmim][CI]) and 1-butylpyridinium chloride ([bpy][CI]); and mixture thereof. Preferably the solvent is butyl acetate, acetonitrile, 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 a) of the process of the present invention, the reaction may be carried out at the temperature of from 0°C to 50°C, preferably from 10°C to 25°C, more preferably at room temperature.
The obtained compound of formula (IV) may be directly used for the next step b) without any treatment, or be isolated by any known process, such as filtration, extraction and/or crystallization, for use in the next step b).
In the step b) of the process of the present invention, the compound of formula (IV) is cyclized to provide the oxazole compound of formula (I). The cyclization may be achieved by heating the compound of formula (IV). Preferably, in the step b) of the process of the present invention, the compound of formula (IV) is heated to the temperature of from 30°C to 200°C, more preferably from 40°C to 180°C, the most preferably from 50°C to 150°C such as 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 and 150°C.
In the step b) of the process of the present invention, the cyclization may be carried out in a solvent. Any solvent that can dissolve the compound of formula (IV) should be suitable. The suitable solvent includes but is not limited to cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME),2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y-butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and Cyrene™; aprotic dipolar solvents such as tetramethylurea, N-formylmorpholine, dimethylformamide (DMF), dimethylacetamide (DMAc), dibutylfromamide, N,N-dimethylbenzamide (DMBA), acetonitrile (ACN), benzonitrile, dimethyl sulfoxide (DMSO), sulfolane, N-methyl-2-pyrrolidone (NMP) and dibutylformamide (DBF); halide solvents such as dichloroethane (DCE), dichloromethane (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] [Cl]); and mixture thereof. Preferably the solvent is DMF, NMP, PC, tetramethylurea, l,3-dimethyl-2-imidazodinone, ACN, sulfolane, triethyl phosphate, y-Butyrolactone and/or N- formylmorpholine. The amount of the solvent used in the cyclization 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 (IV). Preferably, the cyclization in the step b) of the process of the present invention is carried out in the presence of one or more bases. The suitable bases may be selected from alkoxide base such as potassium tert-butoxide (tBuOK), sodium tert-butoxide (tBuONa) and sodium t-pentyloxide (t-pentaONa); other 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), tetramethylguanidine, l,5,7-Triazabicyclo[4,4,0]dec-5-ene (TBD); and inorganic base such as NaH, CaO, KOH, NaOH, Na2CO3, K2CO3, KF/AI2O3, Cs2CO3 and NaNH2; and the mixture thereof. Preferably the base is DBN, DBU, TMG, TBD, NaH, tBuONa, t-pentaONa, CaO, Na2CO3, K2CO3, KF/AI2O3, CS2CO3 and NaNH2, and mixture thereof. The amount of the bases used in the cyclization may be from 0.01 mol to 1 mol, preferably from 0.05 mol to 0.8 mol, more preferably from 0.1 moles to 0.6 moles such as 0.1, 0.2, 0.3, 0.4, 0.5 or 0.6 mole, per 1 mole of the compound of formula (IV).
The cyclization in the process of the present invention may be carried out in the absence of a catalyst. Alternatively, a catalyst may be used to accelerate the cyclization reaction. The catalyst suitable for the cyclization in process of the present invention may be 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 (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 toAg2CO3, 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 (IV).
The obtained oxazole compound of formula (I) may be easily isolated by any known process, such as extraction and/or crystallization. The obtained side-products in the solvent can be easily recycled. In the present invention, the step a) and the step b) of the process may be carried out in one-pot. Accordingly, the present invention also provides a one-pot process for producing the compound of formula (I) which comprises the step a) and the step b) as described above.
As disclosed above, the present invention hereby provides a simple process for producing oxazole compounds, which saves steps and cost, avoids salts by-products, and provides high yield. In addition, the produced side-products can be recycled and further saves the cost of the process.
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 to the grey suspension 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 containing compound 1 (49.68 g, 31.6wt% purity, 92% yield).
1H NMR of E -isomer of compound 3 (400 MHz, DMSO) 6 (ppm): 8.81 (1H), 3.73 (1H), 1.82 (1H).
2H NMR of Z-isomer of compound 3 (400 MHz, DMSO) 6 (ppm): 8.58 (1H), 4.21 (1H), 1.93 (3H). Example 2
The filter cake obtained according to Example 1 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 2 (13.22 g, 98.8wt% purity).
2H NMR of Z-isomer of compound 4 (400 MHz, DMSO) 8 (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 3
To a solution of the compound 2 (2.27 g, 20.0 mmol) in DMF (50 mL) was added N-Bromosuccinimide (2.19 g, 24.6 mmol) portion wise (four portions) within 30 minutes at room temperature. After addition completed, the reaction mixture was stirred at the same condition for additional 2 hours. Then the reaction was quenched by water (20.0 g). The organic phase was separated and dried over anhydrous Na2SO4 and concentrated under vacuum. Then heptane was added to conduct crystallization at 60 °C. After filtration and drying, compound 3 was obtained as yellowish solid (3.36g, 89.1% yield).
NMR data for E-isomer E-2: XH NMR (400 MHz, DMSO-d6) 8 10.03 (m, 1H), 2.45 (s, 3H);
NMR data for Z-isomer Z-2: XH NMR (400 MHz, DMSO-d6) 6 8.53 (m, 1H), 2.26 (s, 3H).
Example 4
To an oven-dried flask charged with compound 3 (8.01 g, 42 mmol) dissolved in butyl acetate (40 ml) were added compound 1 (4.35 g, purity: 91%, 30 mmol). The resulting mixture was stirred at 25°C for 5 hours. The formed precipitate was filtrated and washed by fresh butyl acetate (10 ml) twice, and then dried in vacuum (5-10 mbar) for 2 hours. Assay was determined by qNMR (d6-DMSO). The desired compound 4 was finally collected as white solid (6.69 g, yield: 97%, purity: 90%).
NMR data for E-isomer E-3: XH NMR (400 MHz, DMSO-d6) 8 8.87 (s, 1H), 2.15 (s, 3H);
NMR data for Z-isomer Z-3: TH NMR (400 MHz, DMSO-d6) 8 8.62 (s, 1H), 2.02 (s, 3H).
Example 5
Under N2 atmosphere, compound 4 (211 mg, 1 mmol) was placed in 10 mL reaction tube, then solution of a base (0.2 mmol) in DMF (5 ml) was added. The reaction mixture was stirred at 80°C for 2 hours and then cooled down to room temperature to obtain compound 5. The used bases and yield by HPLC are shown in Table 1.
Table 1
Example 6
Under N2 atmosphere, compound 4 (211 mg, 1 mmol) was placed in 10 mL reaction tube, then solution of DBU (0.2 mmol) in a solvent (5 ml) was added. The reaction mixture was stirred under the reaction condition and then cooled down to room temperature to obtain compound 5. The solvents, the reaction condition (temperature and time) and yield by HPLC are shown in Table 2.
Table 2
Example 7
Under N2 atmosphere, compound 4 (211 mg, 1 mmol) was placed in 10 mL reaction tube, then a solvent (5 ml) was added. The reaction mixture was stirred at 80°C for 4 hours and then cooled down to room temperature to give solution of compound 5. The solvents and yield determined by HPLC are shown in Table 3.
Table 3
Example 8
Under N2 atmosphere, compound 3 (9.59 g, 50 mmol, 98.5%) was dissolved in DMF (50 ml) in a 100 ml round-bottom flask, and then compound 1 (10.92g, 75 mmol, 95%) was added in one portion. The reaction mixture was stirred at 80°C for 1 h and then cooled down to room temperature to obtain the compound 5 in solution (64% yield by HPLC).
Example 9
Under N2 atmosphere, compound 3 and DBU were dissolved in a solvent in a 100 ml round-bottom flask, and then compound 1 was added in one portion. The reaction mixture was stirred at 80°C for 2 h and then cooled down to room temperature to obtain the compound 5. The used amount of materials, solvents and yield determined by HPLC are shown in Table 4.
Table 4

Claims

Claims
1. A process for producing an oxazole compound of formula (I), comprising the steps: a) Reacting a compound of formula (II) with a compound of formula (III) to produce a compound of formula (IV); and b) cyclizing the compound of formula (IV) 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.
2. The process of claim 1, wherein R is H, or lower alkyl optionally substituted by one or more substituents, preferably H or Ci-C6 alkyl optionally substituted by one or more substituents, and more preferably H or methyl or ethyl.
3. The process of claim 1 or 2, wherein in the step a) one or more solvents are used.
4. The process of claim 3, wherein the solvents are selected from the group consisting of cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), 2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y-butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and Cyrene™; aprotic dipolar solvents such as dimethylformamide (DMF), acetonitrile (ACN) and benzonitrile; halide solvents such as dichloroethane (DCE), dichloromethane (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] [Cl]); and mixture thereof. The process of claim 1 or 2, wherein the reaction is carried out at the temperature of from 0°C to 50°C, preferably from 10°C to 25°C, more preferably at room temperature. The process of claim 1 or 2, wherein the obtained compound of formula (IV) from the step a) is directly used in the step b) without any treatment. The process of claim 1 or 2, wherein the cyclization in the step b) is achieved by heating the compound of formula (IV). The process of claim 1 or 2, wherein the cyclization is carried out in a solvent. The process of claim 8, wherein the solvent is selected from the group consisting of cycloalkane such as cyclohexane; alcohol such as methanol, ethanol, n-butanol and 2,2,2-trifluorethanol (TFE); ether such as methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), 2-methyl tetra hydrofuran (Me-THF) and 1,4-dioxane; ester such as ethyl acetate, butylacetate, dimethyl carbonate (DMC), propylene carbonate (PC), triethyl phosphate and y-butyrolactone; ketone such as cyclohexanone, diisopropylketone, l,3-dimethyl-2-imidazodinone and Cyrene™; aprotic dipolar solvents such as tetramethylurea, N-formylmorpholine, dimethylformamide (DMF), dimethylacetamide (DMAc), dibutylfromamide, N,N-dimethylbenzamide (DMBA), acetonitrile (ACN), benzonitrile, dimethyl sulfoxide (DMSO), sulfolane, N-methyl-2-pyrrolidone (NMP) and dibutylformamide (DBF); halide solvents such as dichloroethane (DCE), dichloromethane (DCM) and chloroform; organic bases such as pyridine and quinoline; deep eutectic solvent such as PhCl/urea, AcPhCl/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] [Cl]); and mixture thereof. The process of claim 1 or 2, wherein the cyclization is carried out in the presence of one or more bases. The process of claim 10, wherein the base is selected from the group consisting of alkoxide base such as potassium tert-butoxide (tBuOK), sodium tert-butoxide (tBuONa) and sodium t-pentyloxide (t-pentaONa); other organic base such as l,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,1,3,3-tetramethylguanidine (TMG), tetramethylguanidine, l,5,7-Triazabicyclo[4,4,0]dec-5-ene (TBD); and inorganic base such as NaH, CaO, KOH, NaOH, Na2CO3, K2CO3, KF/AI2O3, CS2CO3 and NaNH2; and the mixture thereof. The process of claim 1 or 2, wherein the cyclization is carried out in the absence of a catalyst. The process of claim 12, wherein the catalyst is selected from the group consisting of any metal catalyst, preferably any Lewis acid salt, for example, those formed by metal element of Group IB, 11 B and VII I B 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 quaternaryammonium 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). The process of claim 11 or 12, wherein the catalyst is selected from the group consisting of 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 process of any one of claims 1-14, wherein the step a) and the step b) are carried out in one- pot.
14
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