CN113336717A - Process for preparing oxazole carboxylic acid esters - Google Patents
Process for preparing oxazole carboxylic acid esters Download PDFInfo
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- CN113336717A CN113336717A CN202110609476.5A CN202110609476A CN113336717A CN 113336717 A CN113336717 A CN 113336717A CN 202110609476 A CN202110609476 A CN 202110609476A CN 113336717 A CN113336717 A CN 113336717A
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- triphenylphosphine
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- dehydrating agent
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- CQHYICHMGNSGQH-UHFFFAOYSA-N 1,3-oxazole-2-carboxylic acid Chemical class OC(=O)C1=NC=CO1 CQHYICHMGNSGQH-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 55
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- -1 imidazole compound Chemical class 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 19
- 150000007530 organic bases Chemical class 0.000 claims abstract description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 3
- 239000011574 phosphorus Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 87
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- PQRKGFMROBZFIM-UHFFFAOYSA-N ethyl 5-ethoxy-4-methyl-1,3-oxazole-2-carboxylate Chemical compound CCOC(=O)C1=NC(C)=C(OCC)O1 PQRKGFMROBZFIM-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- ASWXNYNXAOQCCD-UHFFFAOYSA-N dichloro(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Cl)(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 ASWXNYNXAOQCCD-UHFFFAOYSA-N 0.000 claims description 17
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims description 13
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000004064 recycling Methods 0.000 claims description 6
- PQAMFDRRWURCFQ-UHFFFAOYSA-N 2-ethyl-1h-imidazole Chemical compound CCC1=NC=CN1 PQAMFDRRWURCFQ-UHFFFAOYSA-N 0.000 claims description 5
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 5
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 150000003003 phosphines Chemical class 0.000 claims description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- MYDCBDCRXHZOFQ-UHFFFAOYSA-N triphenylphosphane dihydroiodide Chemical compound I.I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 MYDCBDCRXHZOFQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 150000003017 phosphorus Chemical class 0.000 claims 1
- POXSDSRWVJZWCN-UHFFFAOYSA-N triphenylphosphanium;iodide Chemical compound I.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 POXSDSRWVJZWCN-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 39
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002351 wastewater Substances 0.000 abstract description 2
- 239000000654 additive Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 238000001514 detection method Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- ZFJMTDFOGDGPTF-UHFFFAOYSA-N phosphanium;chloride;hydrochloride Chemical class P.Cl.Cl ZFJMTDFOGDGPTF-UHFFFAOYSA-N 0.000 description 2
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 239000011726 vitamin B6 Substances 0.000 description 2
- 235000019158 vitamin B6 Nutrition 0.000 description 2
- 229940011671 vitamin b6 Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QFYBAGMWAWSMTD-UHFFFAOYSA-N 1h-imidazole;triphenylphosphane Chemical compound C1=CNC=N1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QFYBAGMWAWSMTD-UHFFFAOYSA-N 0.000 description 1
- VQIFBGNOSBKNJI-UHFFFAOYSA-N 4-chloro-n,n-diethylbenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(Cl)C=C1 VQIFBGNOSBKNJI-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- FLGMAMYMYDIKLE-UHFFFAOYSA-N chloro hypochlorite;phosphane Chemical compound P.ClOCl FLGMAMYMYDIKLE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical class P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention relates to the technical field of medicine organic synthesis, and discloses a method for preparing oxazole carboxylate. The method provided by the invention comprises the following steps: in the presence of a catalyst, a dehydrating agent and an organic base, carrying out a cyclization reaction on a compound shown in a formula (II) to obtain a compound shown in a formula (I); the catalyst is an imidazole compound; wherein, in the formula (I) and the formula (II), R1、R2And R3Each independently is a C1-C6 alkyl group. In the invention, the imidazole compound is used as a catalyst for preparing oxazole carboxylic ester, so that the reaction yield can be obviously improved. In addition, the method has simple process, does not relate to the use of other additives, does not generate phosphorus-containing wastewater, belongs to a green process, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of medicine organic synthesis, in particular to a method for preparing oxazole carboxylate.
Background
Oxazole carboxylate is an important medical intermediate, and particularly, oxazole carboxylate (especially 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester) is a key intermediate for synthesizing vitamin B6.
In the early years, oxazole carboxylic acid esters industrially used for the synthesis of vitamin B6 were mainly prepared by the following method:
WO2013163889A, CN104271549B and CN104203929B disclose synthesis methods of using ethyl acetoacetate as a raw material, preparing oxazole through chlorination substitution or oxidation reaction and ring closure reaction,
the preparation of oxazole by the cyclization method of phosphine oxychloride is reported in the journal of the pharmaceutical industry of China (1994, 25, 385-389):
subsequently, the cyclization reaction of the above oxazole carboxylic acid esters has been improved.
CN102060801A discloses an acid-binding agent (R)5) And in the presence of N and a catalyst (N, N-diethylbenzamide compound), dropwise adding an organic solvent of triphosgene to enable the amino acid ester derivative to perform cyclization reaction to obtain the oxazole carboxylic ester compound.
CN111153869A discloses ring closing oxalylated amino acid ester compounds in the presence of organic base, auxiliary agent (such as trihydrocarbyloxyphosphine and arylboronic acid) and phosgene, diphosgene or triphosgene.
The prior art provided above has the technical problems of low reaction yield, being not beneficial to environmental protection and the like, and therefore, a method for preparing oxazole carboxylic ester with simple process steps, environmental friendliness and high yield needs to be found.
Disclosure of Invention
The invention aims to overcome the technical problems of low reaction yield, environmental friendliness and the like in the prior art and provide a method for preparing oxazole carboxylic ester. The method has the advantages of environmental friendliness and high yield.
The inventor of the invention has found through a great deal of research that when the cyclization reaction is carried out on N-ethoxy oxalyl-alpha-alanine ethyl ester, the addition of the imidazole compound plays a very important role, when a catalytic amount of the imidazole compound is added, the reaction rate can be accelerated, the reaction can be carried out more completely, the required reaction temperature is lower than the cyclization reaction temperature reported before, and the conditions are relatively mild. It was found that the addition of imidazole compounds increased the reaction yield to more than 98% and approached quantitative conversion. In addition, by adding catalytic amount of imidazole compound, reaction active intermediate may be imidazole triphenyl phosphonium salt, which is different from the previous dehydration reaction, and the invention provides a chloro cyclization process.
In order to achieve the above object, the present invention provides in a first aspect a process for producing an oxazole carboxylic acid ester comprising: in the presence of a catalyst, a dehydrating agent and an organic base, carrying out a cyclization reaction on a compound shown in a formula (II) to obtain a compound shown in a formula (I); the catalyst is an imidazole compound;
wherein, in the formula (I) and the formula (II), R1、R2And R3Each independently is a C1-C6 alkyl group,
in a second aspect, the present invention provides a process for preparing ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate, comprising: in the presence of a catalyst, a dehydrating agent and organic base, carrying out cyclization reaction on a compound shown in a formula (II) to obtain 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester; the catalyst is an imidazole compound;
wherein the catalyst is at least one selected from imidazole, 2-methylimidazole and 2-ethylimidazole; the dehydrating agent is triaryl substituted phosphine dihalide and is at least one selected from triphenylphosphine dichloride, triphenylphosphine dibromide and triphenylphosphine diiodide; the organic base is organic amine and is selected from at least one of triethylamine, tripropylamine and tributylamine;
preferably, the conditions of the ring closure reaction include: the temperature is 20-60 ℃; the time is 0.2-2 h;
preferably, the molar ratio of the compound represented by formula (II), the catalyst, the dehydrating agent and the organic base is 1: (0.01-0.03): (1-1.5): (2-3).
Compared with the prior art, the invention adopts the imidazole compound as the catalyst for preparing the oxazole carboxylic ester, and can obviously improve the reaction yield. In addition, in a preferred embodiment of the invention, for example, trisubstituted phosphine oxide generated in the cyclization reaction can be regenerated into trisubstituted phosphine dichloride for recycling after being treated by triphosgene or phosgene, and generated organic amine hydrochloride is recycled after being treated by sodium hydroxide, and only carbon dioxide and sodium chloride are byproducts in the whole process. In addition, the reaction yield of the invention is up to more than 98%, the process is simple, the use of other auxiliary agents is not involved, the phosphorus-containing wastewater is not generated, the invention belongs to a green process, and the industrial production is facilitated.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In order to achieve the above object, the present invention provides in a first aspect a process for producing an oxazole carboxylic acid ester comprising: in the presence of a catalyst, a dehydrating agent and an organic base, carrying out a cyclization reaction on a compound shown in a formula (II) to obtain a compound shown in a formula (I); the catalyst is an imidazole compound;
wherein, in the formula (I) and the formula (II), R1、R2And R3Each independently is one of C1-C6 alkyl,
according to some embodiments of the invention, in formula (I) and formula (II), R1、R2And R3Each independently is a C1-C4 alkyl group.
In the present invention, the compound represented by the formula (II) can be obtained commercially, or can be prepared in the following manner (taking N-ethoxyoxalyl- α -alanine ethyl ester as an example): mixing alanine, oxalic acid and ethanol in a ratio of 1: (1.2-1.8): (5-15) adding a water-carrying agent (such as benzene) into the system, and carrying out dehydration reaction at 65-100 ℃ for 24-48 h.
According to some embodiments of the invention, the conditions of the ring closure reaction may comprise: the temperature is 10-100 deg.C (10 deg.C, 20 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C, 100 deg.C or any value therebetween), preferably 20-60 deg.C; the time is 0.1-10h, preferably 0.2-2 h.
According to some embodiments of the invention, the molar ratio of the compound of formula (II), the catalyst, the dehydrating agent and the organic base may be 1: (0.005-0.1): (0.8-2): (2-3); preferably 1: (0.01-0.03): (1-1.5): (2-3).
According to some embodiments of the invention, the imidazole-based compound has a structural formula as shown in formula (III):
in the formula (III), R4、R5And R6Each independently selected from C1-C6 alkyl or C6-C10 aryl.
According to some embodiments of the invention, R4、R5And R6Each independently selected from C1-C4 alkyl or C6-C8 aryl.
According to some embodiments of the invention, the catalyst is selected from at least one of imidazole, 2-methylimidazole and 2-ethylimidazole.
According to some embodiments of the present invention, the dehydrating agent may be a substituted phosphine dihalide selected from at least one of triphenylphosphine dichloride, triphenylphosphine dibromide and triphenylphosphine diiodide; preferably triphenylphosphine dichloride.
According to some embodiments of the present invention, the organic base may be selected from at least one of triethylamine, tripropylamine, and tributylamine; triethylamine is preferred.
According to some embodiments of the present invention, the cyclization reaction is carried out in the presence of an organic solvent, which may be selected from at least one of alkanes of C1-C8, aromatics of C6-C8, and chlorobenzene; preferably at least one selected from the group consisting of C6-C8 alkanes (e.g., heptane, octane), toluene, xylene and chlorobenzene.
According to some embodiments of the present invention, the organic solvent may be used in an amount of 1 to 20mL, preferably 2 to 10mL, relative to 1g of the compound represented by formula (II).
The post-treatment of the cyclization reaction in the present invention is not particularly limited, and can be carried out in a manner conventional in the art. The work-up can be carried out, for example, in the following manner (taking the preparation of ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate as an example): carrying out solid-liquid separation (for example, filtration) on the reacted system to obtain a solid (triphenyl phosphine oxide which can be further prepared into triphenyl phosphine dichloride for recycling) and a filtrate; standing and layering the filtrate to obtain an organic phase and a water phase, extracting the water phase with a solvent (such as toluene), then combining the organic phases, and distilling under reduced pressure at-0.5 MPa to-0.05 MPa to remove and recover the solvent (such as toluene) to obtain a pure target compound (4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester); the residual water phase is treated by alkali (such as sodium hydroxide) to obtain organic base (such as triethylamine) which can be further recycled and reused.
In the present invention, in order to obtain a better effect, the addition step of the cyclization reaction may be performed in the following manner:
the catalyst, the compound represented by the formula (II) (oxalyl compound) and triethylamine are mixed in an organic solvent (for example, toluene), a solution containing a dehydrating agent (for example, triphenylphosphine dichloride) obtained by dissolving triphenylphosphine dichloride in an organic solvent is added dropwise to the above system or a continuous flow of the above system is mixed with a solution containing a dehydrating agent (for example, triphenylphosphine dichloride), and a cyclization reaction is carried out at 20 to 60 ℃.
In a second aspect, the present invention provides a process for preparing ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate, comprising: in the presence of a catalyst, a dehydrating agent and organic base, carrying out cyclization reaction on a compound shown in a formula (II) to obtain 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester; the catalyst is an imidazole compound;
wherein the catalyst is at least one selected from imidazole, 2-methylimidazole and 2-ethylimidazole; the dehydrating agent is triaryl substituted phosphine dichloride selected from triphenyl phosphorus dichloride; the organic base is organic amine and is selected from at least one of triethylamine, tripropylamine and tributylamine;
preferably, the conditions of the ring closure reaction include: the temperature is 20-60 ℃; the time is 0.2-2 h;
preferably, the molar ratio of the compound represented by formula (II), the catalyst, the dehydrating agent and the organic base is 1: (0.01-0.03): (1-1.5): (2-3).
According to some embodiments of the invention, the cyclization reaction also provides triaryloxyphosphorus and organic amine hydrochloride.
According to some embodiments of the invention, the method further comprises: and (3) reacting triarylphosphine oxide obtained by the cyclization reaction with at least one of triphosgene, diphosgene and phosgene to obtain triarylphosphine dichloride for cyclic use, namely recycling for the cyclization reaction.
In the present invention, the reaction conditions for preparing triarylphosphine dichloride from triarylphosphine oxide and triphosgene, diphosgene or phosgene are not particularly limited, and can be performed according to the conventional manner in the field, for example, the following manner: triphenylphosphine oxide is reacted with a chlorinating agent (e.g. triphosgene, diphosgene or phosgene) at a temperature of 70-90 deg.C. Preferably, this is done as follows: a solution containing a chlorinating agent is added dropwise to a solution containing triphenylphosphine oxide (the solvent may be toluene) at 70-90 deg.C.
According to some embodiments of the invention, the method further comprises: reacting the organic amine hydrochloride obtained by the cyclization reaction with inorganic base to obtain organic amine, and recycling the organic amine, namely recycling the organic amine for the cyclization reaction; the inorganic base is at least one selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.
The reaction conditions of the organic amine hydrochloride and the inorganic base are not particularly limited in the present invention, and can be carried out in a manner conventional in the art.
The present invention will be described in detail below by way of examples.
In the following examples and comparative examples, the starting materials, bases, and solvents used were all obtained commercially without specific description. In the following examples, the reaction progress was followed by Gas Chromatography (GC) to follow the reaction and yield determination.
Analytical conditions for Gas Chromatography (GC): a chromatographic column: SE-30M, column temperature: 190 ℃, detector TCD: 260 ℃, injection port temperature: at 200 ℃.
Example 1
To a 2L three-necked reaction flask equipped with a magnetic stirrer, a thermometer and a dropping funnel, ethyl N-ethoxyoxalyl-. alpha. -alanine (100g, 0.461mol), 2-methylimidazole (0.95g, 0.012mol), triethylamine (128.46g, 1.272mol) and 300mL of toluene were sequentially added at 30 ℃ and uniformly stirred, and a solution of triphenylphosphorodichloridate (200g, 0.6mol) and toluene (500mL) was added dropwise at 30 ℃ to perform cyclization reaction at 30 ℃ for 15min, and the conversion of ethyl N-ethoxyoxalyl-. alpha. -alanine was 99.4% by gas phase detection. After the reaction is finished, 200mL of water is added, the mixture is filtered to obtain a solid and a filtrate, the solid is triphenylphosphine oxide, vacuum drying (-0.09MPa) is carried out at the temperature of 60 ℃ to obtain the triphenylphosphine oxide (150.8g, 0.54mol), the triphenylphosphine oxide is added into a 2L three-mouth reaction bottle, then 350mL of toluene is added, the mixture is heated to 80 ℃ under an oil bath and stirred to be dissolved, triphosgene (63g, 0.212mol, dissolved in 100mL of toluene) solution is dropwise added, the dripping is finished for 1h, then the heat preservation reaction is continued for 1h at the temperature of 80 ℃ to obtain the toluene solution of triphenylphosphine dichloride (containing 0.489mol of triphenylphosphine), and the toluene solution can be circularly used for the cyclization reaction of N-ethoxyoxalyl-alpha-alanine ethyl ester. The filtrate is separated into layers, the water layer is extracted by toluene (50mL multiplied by 2), the pH of the extracted water layer is adjusted to 12 by adding 30 percent sodium hydroxide solution, and triethylamine is recovered by distillation and can be used for cyclization reaction of N-ethoxy oxalyl-alpha-alanine ethyl ester; the organic phase was distilled under reduced pressure at a vacuum degree of-0.098 MPa to remove and recover toluene, to give 90.8g of a cyclized product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) having a purity of 99.8% by weight and a yield of 98.8% (based on ethyl N-ethoxyoxalyl-. alpha. -alanine).
Nuclear magnetic data of the product:1H-NMR(400MHz,CDCl3)4.43-4.36(q，2H),4.35-4.28(q，2H),2.10(s，3H),1.41(t，6H)。
example 2
To a 2L three-necked reaction flask equipped with a magnetic stirrer, a thermometer and a dropping funnel, ethyl N-ethoxyoxalyl-. alpha. -alanine (100g, 0.461mol), 2-methylimidazole (0.38g, 0.005mol), triethylamine (97.8g, 0.968mol) and 300mL of toluene were added in this order at 60 ℃ and a solution of triphenyl phosphorochloridate (169g, 0.507mol) and toluene (500mL) was added dropwise at 60 ℃ to conduct cyclization reaction for 1 hour at 60 ℃ and the conversion of ethyl N-ethoxyoxalyl-. alpha. -alanine was 99.2% by gas phase detection. After the reaction is finished, cooling to room temperature, adding 200mL of water, filtering to obtain a solid and a filtrate, wherein the solid is triphenylphosphine oxide, performing vacuum drying (-0.09MPa) at 60 ℃ to obtain 128.3g (0.461mol) of the triphenylphosphine oxide, adding the triphenylphosphine oxide into a 2L three-mouth reaction bottle, then adding 350mL of toluene, heating to 80 ℃ under an oil bath, stirring and dissolving, dropwise adding a solution of triphosgene (53g, 0.179mol, dissolved in 100mL of toluene) at 80 ℃, completing dropwise adding for 1h, and then continuing to perform heat preservation reaction for 1h at 80 ℃ to obtain a toluene solution of triphenylphosphine dichloride (containing 0.415mol of the triphenylphosphine dichloride), and the solution can be circularly used for cyclization reaction of N-ethoxyoxalyl-alpha-alanine ethyl ester. The filtrate is separated into layers, the water layer is extracted by toluene (50mL multiplied by 2), the pH of the extracted water layer is adjusted to 12 by adding 30 percent sodium hydroxide solution, and triethylamine is recovered by distillation and can be used for cyclization reaction of N-ethoxy oxalyl-alpha-alanine ethyl ester; the organic phase was vacuum-distilled at-0.098 MPa to remove and recover toluene, and 90.6g of a cyclization product (4-methyl-5-ethoxyoxazole-2-carboxylic acid ethyl ester) was obtained with a purity of 99.5% by weight and a yield of 98.3%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 3
To a 2L three-necked reaction flask equipped with a magnetic stirrer, a thermometer and a dropping funnel, ethyl N-ethoxyoxalyl-. alpha. -alanine (100g, 0.461mol), 2-methylimidazole (1.135g, 0.0138mol) and triethylamine (97.8g, 0.968mol) were sequentially added in 300mL of toluene at 25 ℃ and a solution of triphenyl phosphorochloridate (169g, 0.507mol) and toluene (500mL) was added dropwise at 25 ℃ to conduct a cyclization reaction at 25 ℃ for 0.5h, and the conversion of ethyl N-ethoxyoxalyl-. alpha. -alanine was 99.6% by gas phase detection. After the reaction is finished, 200mL of water is added, filtration is carried out to obtain a solid and a filtrate, the solid is triphenylphosphine oxide, vacuum drying (-0.09MPa) is carried out at 60 ℃ to obtain 128.9g (0.463mol) of the triphenylphosphine oxide, the triphenylphosphine oxide is added into a 2L three-mouth reaction bottle, then 350mL of toluene is added, the solution is stirred and dissolved when the solution is heated to 80 ℃ under oil bath, triphosgene (53.2g, 0.179mol, dissolved in 100mL of toluene) solution is dropwise added at 80 ℃ for 1h, then the heat preservation reaction is continued for 1h at 80 ℃ to obtain toluene solution of triphenylphosphine dichloride (containing 0.420mol of triphenylphosphine dichloride), and the toluene solution can be circularly used for cyclization reaction of N-ethoxy oxalyl-alpha-alanine ethyl ester. The filtrate is separated into layers, the water layer is extracted by toluene (50mL multiplied by 2), the pH of the extracted water layer is adjusted to 12 by adding 30 percent sodium hydroxide solution, and g triethylamine is recovered by distillation and can be used for cyclization reaction of N-ethoxy oxalyl-alpha-alanine ethyl ester; the organic phase was vacuum-distilled at-0.098 MPa to remove and recover toluene, and 91.2g of a cyclization product (4-methyl-5-ethoxyoxazole-2-carboxylic acid ethyl ester) was obtained with a purity of 99.7 wt% and a yield of 99.0%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 4
The procedure is as in example 1, except that 2-methylimidazole is replaced by an equimolar amount of imidazole.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 99.4%, yielding 90.8g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 98.3% by weight and a yield of 97.3%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 5
The procedure is as in example 1, except that 2.3mmol of 2-methylimidazole are added.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 95.4%, yielding 88.1g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 97.5 wt% in 93.6% yield.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 6
The procedure is as in example 1, except that 2-methylimidazole is added in a molar amount of 46 mmol.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 99.1%, yielding 90.5g of the cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 99.5% by weight and a yield of 98.1%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 7
The procedure is as in example 1, except that recovered triphenylphosphine dichloride is used.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 99.3%, yielding 90.9g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 99.6% by weight and a yield of 98.6%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 8
The procedure is as in example 1, except that the temperature of the cyclization reaction is 10 ℃.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 92.1%, yielding 65.2g of the cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 90.7% by weight and a yield of 64.4%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Example 9
The procedure is as in example 1, except that the temperature of the cyclization reaction is 100 ℃.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 98.5%, giving 89.7g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate), purity 94.3% by weight, yield 92.1%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Comparative example 1
The procedure is as in example 1, except that no catalyst is added.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 92.6%, yielding 86.8g of the cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 95.3% by weight and a yield of 90.2%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Comparative example 2
The procedure is as in example 1, except that 2-methylimidazole is replaced by an equimolar amount of N, N-diethyl-p-chlorobenzamide.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 96.1%, yielding 87.3g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 97.6 wt% in a yield of 92.8%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
Comparative example 3
The procedure is as in example 1, except that 2-methylimidazole is replaced by an equimolar amount of phenylboronic acid.
Finally, the conversion of N-ethoxyoxalyl- α -alanine ethyl ester was 95%, yielding 85.1g of a cyclization product (ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate) with a purity of 93.1% by weight and a yield of 96.4%.
The nuclear magnetic detection result is 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (10)
1. A process for preparing an oxazole carboxylic acid ester comprising: in the presence of a catalyst, a dehydrating agent and an organic base, carrying out a cyclization reaction on a compound shown in a formula (II) to obtain a compound shown in a formula (I); the catalyst is an imidazole compound;
wherein, in the formula (I) and the formula (II), R1、R2And R3Each independently is a C1-C6 alkyl group,
2. the method according to claim 1, wherein in formula (I) and formula (II), R1、R2And R3Each independently is a C1-C4 alkyl group;
and/or, the conditions of the ring closure reaction include: the temperature is 10-100 ℃, and the preferable temperature is 20-60 ℃; the time is 0.1-10h, preferably 0.2-2 h.
3. The process according to claim 1 or 2, wherein the molar ratio of the compound represented by formula (II), the catalyst, the dehydrating agent and the organic base is 1: (0.005-0.1): (0.8-2): (2-3); preferably 1: (0.01-0.03): (1-1.5): (2-3).
4. A method according to any one of claims 1 to 3 wherein the imidazole compound has the formula (III):
in the formula (III), R4、R5And R6Each independently selected from C1-C6 alkyl or C6-C10 aryl;
preferably, R4、R5And R6Each independently selected from C1-C4 alkyl or C6-C8 aryl;
more preferably, the catalyst is selected from at least one of imidazole, 2-methylimidazole and 2-ethylimidazole.
5. The method according to any one of claims 1 to 4, wherein the dehydrating agent is a substituted phosphine dihalide selected from at least one of triphenylphosphine dichloride, triphenylphosphine dibromide and triphenylphosphine iodide; preferably triphenylphosphine dichloride.
6. The process according to any one of claims 1 to 5, wherein the organic base is selected from at least one of triethylamine, tripropylamine and tributylamine; triethylamine is preferred.
7. The process of any one of claims 1 to 6, wherein the ring closure reaction is carried out in the presence of an organic solvent selected from at least one of C6-C8 alkanes, C6-C8 aromatics, and chlorobenzene; preferably at least one selected from heptane, octane, toluene, xylene and chlorobenzene.
8. The process according to claim 7, wherein the amount of the organic solvent used is 1 to 20mL, preferably 2 to 10mL, relative to 1g of the compound represented by formula (II).
9. A process for the preparation of ethyl 4-methyl-5-ethoxyoxazole-2-carboxylate comprising: in the presence of a catalyst, a dehydrating agent and organic base, carrying out cyclization reaction on a compound shown in a formula (II) to obtain 4-methyl-5-ethoxy oxazole-2-carboxylic acid ethyl ester; the catalyst is an imidazole compound;
wherein the catalyst is selected from at least one of imidazole, 2-methylimidazole and 2-ethylimidazole; the dehydrating agent is triaryl substituted phosphorus dihalide; at least one member selected from the group consisting of triphenylphosphine dichloride, triphenylphosphine dibromide and triphenylphosphine diiodide; the organic base is organic amine and is selected from at least one of triethylamine, tripropylamine and tributylamine;
preferably, the conditions of the ring closure reaction include: the temperature is 20-60 ℃; the time is 0.2-2 h;
preferably, the molar ratio of the compound represented by formula (II), the catalyst, the dehydrating agent and the organic base is 1: (0.01-0.03): (1-1.5): (2-3).
10. The process of claim 9, wherein the ring closure reaction further yields triaryloxyphosphorus and an organic amine hydrochloride;
preferably, the method further comprises: reacting triarylphosphine oxide obtained by the cyclization reaction with at least one of triphosgene, diphosgene and phosgene to obtain triarylphosphine dichloride for cyclic use;
preferably, the method further comprises: reacting the organic amine hydrochloride obtained by the cyclization reaction with inorganic base to obtain organic amine, and recycling; the inorganic base is at least one selected from sodium hydroxide, potassium hydroxide and lithium hydroxide.
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