CN104529935B - Method for synthesizing ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate - Google Patents
Method for synthesizing ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 230000002194 synthesizing effect Effects 0.000 title abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 title abstract 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 104
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims abstract description 13
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 claims abstract description 12
- VDTNKXSVUGXUOJ-UHFFFAOYSA-N chembl2441358 Chemical compound NC(=S)C1=CC=C(O)C=C1 VDTNKXSVUGXUOJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006170 formylation reaction Methods 0.000 claims abstract description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims abstract description 9
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 18
- 239000011593 sulfur Substances 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 238000005917 acylation reaction Methods 0.000 claims description 17
- -1 2- chloroacetyl Chemical group 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 12
- 238000010189 synthetic method Methods 0.000 claims description 11
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- QBNJPSHRAWSBDW-UHFFFAOYSA-N 2-methylpropane;hydrobromide Chemical compound Br.CC(C)C QBNJPSHRAWSBDW-UHFFFAOYSA-N 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 239000001117 sulphuric acid Substances 0.000 claims description 7
- 235000011149 sulphuric acid Nutrition 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 6
- 230000000977 initiatory effect Effects 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 235000010299 hexamethylene tetramine Nutrition 0.000 claims description 5
- 239000004312 hexamethylene tetramine Substances 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 2
- JFYIBFCXQUDFQE-UHFFFAOYSA-N 2-hydroxybenzenecarbothioamide Chemical compound NC(=S)C1=CC=CC=C1O JFYIBFCXQUDFQE-UHFFFAOYSA-N 0.000 claims 1
- CGKQZIULZRXRRJ-UHFFFAOYSA-N Butylone Chemical compound CCC(NC)C(=O)C1=CC=C2OCOC2=C1 CGKQZIULZRXRRJ-UHFFFAOYSA-N 0.000 claims 1
- 241001597008 Nomeidae Species 0.000 claims 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 238000000605 extraction Methods 0.000 claims 1
- AGGKEGLBGGJEBZ-UHFFFAOYSA-N tetramethylenedisulfotetramine Chemical compound C1N(S2(=O)=O)CN3S(=O)(=O)N1CN2C3 AGGKEGLBGGJEBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 21
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 abstract 2
- 239000007795 chemical reaction product Substances 0.000 abstract 2
- 239000007858 starting material Substances 0.000 abstract 1
- 238000005636 thioacylation reaction Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000005265 energy consumption Methods 0.000 description 6
- 238000003912 environmental pollution Methods 0.000 description 5
- 229960004011 methenamine Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002912 waste gas Substances 0.000 description 5
- 239000002351 wastewater Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000703 high-speed centrifugation Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000007039 two-step reaction Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000010719 annulation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003317 industrial substance Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012264 purified product Substances 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WSASYMPVLSOFOW-UHFFFAOYSA-N C(C)CC(CC(=O)O)=O.ClC=C Chemical compound C(C)CC(CC(=O)O)=O.ClC=C WSASYMPVLSOFOW-UHFFFAOYSA-N 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- RRTCFFFUTAGOSG-UHFFFAOYSA-N benzene;phenol Chemical compound C1=CC=CC=C1.OC1=CC=CC=C1 RRTCFFFUTAGOSG-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000007265 chloromethylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- VQMZQVCNWYKCQD-UHFFFAOYSA-N ethyl formate 1,3-thiazole Chemical compound C(=O)OCC.S1C=NC=C1 VQMZQVCNWYKCQD-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 1
- 229960003019 loprazolam Drugs 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical class CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention provides a method for synthesizing high-purity ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate. The method comprises the following steps of carrying out thioacylation reaction on p-cyanophenol and thioacetamide as starting materials to obtain 4-hydroxythiobenzamide (II), directly carrying out thiazole reaction on the reaction product which is not separated and separating to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole formate (III); carrying out formylation reaction on the compound as shown in the formula (III) to obtain ethyl 2-(3-carbaldehyde-4-hydroxyphenyl)-4-methyl-5-thiazole formate (IV), directly carrying out isobutylation reaction on the reaction product which is not separated to obtain ethyl 2-(3-aldehyde-4-isobutyloxyphenyl)-4-methylthiazole-5-formate (I) of which the purity is equal to or greater than 99% and the content is equal to or greater than 99%. The production process is optimized and thus the quality of the product is greatly improved and the high yield is achieved.
Description
(1) technical field
The present invention relates to the synthesis of Febustat intermediate, and in particular to high-purity 2- (3- aldehyde radical -4- isobutyl phenyl ethers
Base) -4- methylthiazole-5-carboxylates synthetic method.
(2) background technology
2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates are the passes for producing medicine Febustat
Key intermediate, its structural formula is：
Patent CN103880775A (201210563201.3) document has had been reported that can be with 4-hydroxybenzonitrile as initial former
Material, is obtained through isobutyl, chloromethylation, hydrolysis, oxidation, sulfonyl, ring-closure reaction, but its step is tediously long, and step by step
Process, consumption of raw materials is increased, cause pollution larger, and the product content and yield that finally obtain are all low, its synthetic route is such as
Under：
1st, above-mentioned technique employs six-step process and just obtains final product, and step is tediously long, and often step will be separated, and pollutes
Greatly, high energy consumption, yield are low, and cost pressure is big.
2nd, substantial amounts of chemical raw material used in course of reaction, but conversion ratio is low, easily produce substantial amounts of waste residue；Solvent
Species is more and measures big, it is not easy to reclaim；And substantial amounts of waste water is produced, pollute very big.
3rd, product quality often can only achieve purity more than 90%, it is difficult to meet the demand of high-end customer.
Patent CN102086169B (ZL200910191710.6) discloses a kind of intermediate of Febustat such as 2- (3- first
Aldehyde radical -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters preparation method.The method with thioacetamide, to cyano group benzene
Phenol is reaction raw materials, the reacted prepared 4- hydroxythiobenzamides in concentrated hydrochloric acid aqueous solution, by itself and 2- chloroethene ethyl acetoacetic acids
Ethyl ester reaction prepares 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters, and the compound is with hexamethylenetetramine in poly
Reaction in the presence of phosphoric acid and Loprazolam obtains 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters.Should
Patented method：(1) 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters are obtained using two-step method, often step reaction needs to divide
Product can just be obtained from purification, while the detached product of the first step also needs to drying, substantial amounts of waste water, waste gas is produced, increased energy
Consumption, easily causes environmental pollution.(2) first step sulfonyl reaction yield about 90%, second step annulation yield about 85%, two
Step yield about more than 76.5%, yield is relatively low.(3) do not react including isobutyl in the patented method, but from patent
From the point of view of itself, it is also desirable to isolate 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters, could be further
For synthesizing 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates, the substantial amounts of waste water of process generation,
Waste gas, increases energy consumption, easily causes environmental pollution.
Patent application CN101412699A (200710047267.6) discloses a kind of 2- (3- carboxaldehyde radicals -4- hydroxy benzeness
Base) -4- methyl-5-thiazole formic acid ethyl esters preparation method, the course of reaction of the method is as follows：With 4-hydroxybenzonitrile and thio second
Amide is raw material, reacts the 4- hydroxythiobenzamides for obtaining, gained 4- hydroxythiobenzamides and 2- chloroethene ethyl acetoacetic acids
Ethyl ester reaction obtains 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters, then 2- (4- hydroxy phenyls) -4- methyl -5-
Thiazole ethyl formate obtains 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid second with hexamethylenamine reaction again
Ester, in the preparation technology, 4- hydroxythiobenzamides and 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters
Successively separately synthesized step by step, i.e., then first separately synthesized 4- hydroxythiobenzamides are raw material with which in non-acidic environment
In further synthesize 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters, it is to avoid the latter during the course of the reaction from status
Solution.The patent preparation method：(1) sulfur acylation reaction needs 48 hours, and the formylation reaction time needs 24 hours, and the response time is very
Long, efficiency is low.(2) 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters are obtained using two-step method, often step reaction needs
Separating-purifying can just obtain product, while the detached product of the first step also needs to drying, produce substantial amounts of waste water, waste gas, increase
Energy consumption, easily causes environmental pollution.(3) first step sulfonyl reaction yield about 87.6%, second step annulation yield is about
80.6%, two step yields about more than 67%, yield is low.(4) sulfur acylation reaction makees solvent using the DMF of height boiling, reclaims a large amount of
Solvent, energy consumption is very high, and environmental pollution is big.(5) patented method is not reacted including isobutyl, but comes from patent itself
See, it is also desirable to isolate 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters, can just be further used for closing
Into 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates, the process produces substantial amounts of waste water, waste gas,
Increase energy consumption, easily cause environmental pollution.
(3) content of the invention
Present invention is generally directed to the deficiency of above synthetic method, there is provided a kind of technological process is short, reaction is complete, yield
The high, conjunction of 2- (3- aldehyde radical -4- the isobutoxy phenyls) -4- methylthiazole-5-carboxylates that waste gas sewage discharge is low, purity is high
Into method.The method synthetic route is short, it is not necessary to which often step is separated, and operation is simple, takes short, high income, pollutes little, it is easy to
Industrialized production.
For achieving the above object, technical scheme is as follows：
The present invention carries out sulfur acylation reaction by initiation material and thioacetamide of 4-hydroxybenzonitrile, obtains structure formula (II)
4- hydroxythiobenzamides；Be not required to it is to be separated, directly in reaction system plus 2- chloroacetyl acetacetic esters carry out thiazole
Reaction, obtains the thiazole (2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters) of structure formula (III), centrifugation point
From；Isolated 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III) carries out first with hexamethylenetetramine
Acylation reaction, obtains 2- (3- carboxaldehyde radicals -4- the hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters of structure formula (IV)；Need not
Separate, being directly added into isobutane bromide carries out isobutyl reaction, obtains highly purified 2- (3- aldehyde radical -4- isobutyl phenyl ethers
Base) -4- methylthiazole-5-carboxylates (Formulas I), purity >=99%, content >=99%.
2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylate structure formula (I)s：
4- hydroxythiobenzamide structure formula (II)s：
The structure formula (III) of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters：
The structure formula (IV) of 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters：
The specific implementation step of the present invention is as follows：
Step (1) sulfur acylation reaction, with cyanophenol as initiation material, carries out sulfur acylation reaction, sulfur with thioacetamide
It is 1.1～4.2 for the mol ratio of acetamide and 4-hydroxybenzonitrile:1, reaction temperature 40-80 DEG C, response time are 2-8 hours, are made
The product of 4- hydroxythiobenzamides (Formula II) must be contained；The sulfur acylation reaction is carried out in anhydrous phosphoric acid system,
The proportioning of the anhydrous phosphoric acid system being configured to polyphosphoric acids plus suitable quantity of water, wherein polyphosphoric acids and water, containing with polyphosphoric acids
On the basis of amount, polyphosphoric acids：The weight ratio of water is 20：1～2；
In above-mentioned course of reaction, using anhydrous phosphoric acid system, polyphosphoric acids system viscosity is overcome greatly, mixing effect difference
Shortcoming, while ensure that anhydrous system reacts, provides condition for subsequent two-step reaction one pot process, improves yield,
And quality is good.
Step (2) thiazoleization is reacted, the product containing 4- hydroxythiobenzamides that above-mentioned reaction is obtained, it is not necessary to
Separate, i.e. sulfur acylation reaction direct next step thiazoleization reaction after terminating is directly added into organic solvent alcohol in reaction system
Class diluting reaction system, forms anhydrous phosphoric acid+alcohols system, and being subsequently adding 2- chloroacetyl acetacetic esters carries out thiazole reaction,
Controlling reaction temperature 30-80 DEG C, response time 3-6 hour；After reaction terminates, add water crystallize, filters, uses ice ethanol rinse, obtain
To thiazole 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)；
Due to the present invention reactions steps (1) product be not required to it is to be separated, be directly entered step (2) reaction, so by control
The mol ratio of 2- chloroacetyl acetacetic esters processed and initial substance is determining inventory；That is 2- chloroacetyl acetacetic esters：To cyano group benzene
The mol ratio 1.1～3.5 of phenol：1；
The one kind of the organic solvent alcohols being directly added in above-mentioned reaction system in methanol or ethanol, polyphosphoric acids：
Alcohols：The weight ratio of 4-hydroxybenzonitrile is 2～8：2～7.5：1.
Step (3) formylation reaction, with polyphosphoric acids plus sulphuric acid or phosphoric acid as reaction dissolvent, adds in the reaction dissolvent
Hexamethylenetetramine, and 2- (4- the hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters that above-mentioned reactions steps (2) are isolated
(formula III) carries out formylation reaction, and reaction temperature is 60-120 DEG C, response time 3-10 hour；After reaction terminates, water is added
And organosilane ester extracting and demixing, organic layer is concentrated to dryness (substantially no fraction is steamed), obtains the compound of formula (IV) containing structure
Reaction mass, it is not necessary to separate, is directly entered next step reaction；
In the reaction mass of step (3), the content of formula IV compound is more than 95%；
Wherein hexamethylenetetramine：The mol ratio of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
For 1.1～3.5：1；
In step (3) reaction, before the reaction, reaction dissolvent is first prepared, sulphuric acid or phosphorus are initially charged in polyphosphoric acids
Acid, adds reacting substance, it is possible to increase mixing effect；Wherein polyphosphoric acids：Sulphuric acid (or phosphoric acid)：2- (4- hydroxy phenyls)-
The weight ratio of 4- methyl-5-thiazole formic acid ethyl esters (formula III) is 1～10：0.2～0.5：1；
After the step (3) reaction terminates, extracted with water and organosilane ester, described organosilane ester be selected from butyl acetate or
One kind in ethyl acetate, wherein organosilane ester：Water：2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
Weight ratio be 3～8：2～7.5：1.
Step (4) isobutyl reacts, and using DMF or DMSO as reaction dissolvent, changes step (3) obtained containing formula (IV)
The material of compound is molten clear, adds nertralizer, and adding isobutane bromide carries out isobutyl reaction, and the response time is that 3-10 is little
When, reaction temperature is 60-115 DEG C；Add water precipitation, cools to 10-30 DEG C, centrifugation, and rinsing obtains highly purified product 2- (3- aldehyde
Base -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates (Formulas I), purity >=99%, content >=99%；
Due to the present invention reactions steps (3) product be not required to it is to be separated, be directly entered step (4) reaction, so, by control
Isobutane bromide processed and step (3) initial substance 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl ester (formula III) rub
You compare to determine inventory, wherein isobutane bromide：2-'s (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
Mol ratio is 1.1～4.5：1；
The one kind of the reaction dissolvent of step (4) the isobutyl reaction in DMF or DMSO, reaction dissolvent DMF (or
DMSO)：The envelope-bulk to weight ratio of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III) is 3～8L：1kg；
The one kind of the nertralizer in potassium carbonate or sodium carbonate, nertralizer：2- (4- hydroxy phenyls) -4- methyl -5-
The mol ratio of thiazole ethyl formate (formula III) is 0.5～1：1；
After step (4) the isobutyl reaction terminates, add water in product precipitation target product, wherein water：2-(4-
Hydroxy phenyl) -4- methyl-5-thiazole formic acid ethyl esters (formula III) weight ratio be 2～4：1；
After step (4) the isobutyl reaction terminates, centrifugation, rinsing process are first rinsed once with organic solvent DMF,
Water is rinsed twice again, and last methanol solvate is rinsed twice, obtains highly purified product 2- (3- aldehyde radical -4- isobutoxy phenyls) -4-
Methylthiazole-5-carboxylate (Formulas I).
Synthetic method of the present invention, all obtains unexpected effect at aspects such as product purity, technological process, production costs
Really, the present invention compared with prior art, with outstanding feature and progress：
(1) synthesis technique flow process is short, and traditional reactions steps are six steps, and the present invention is reduced to four steps；
(2) synthetic method is simple, and traditional handicraft is often walked after needs are separated and just carries out rear single step reaction, and the present invention is reduced to two
After secondary separating step, i.e. sulfur acylation reaction are complete, it is not necessary to separate, the reaction of next step thiazoleization is directly carried out；Formylation reaction
After completely, it is not necessary to separate, directly carry out next step isobutyl reaction, obtain purpose product；
(3) sulfur acylation reaction is carried out in anhydrous phosphoric acid system, is compared with common sour water dicyandiamide solution, the nothing of the present invention
Water Phosphoric Acid overcomes polyphosphoric acids system viscosity greatly, the shortcoming of mixing effect difference, while ensure that anhydrous system reacts,
Condition is provided for subsequent two-step reaction one pot process, while improve yield；
(4) solvent species and consumption are reduced；The present invention is reduced very for first patent in technical background
Multi-solvent, because it needs six-step process, with respect to the quantity of solvent that latter two patents are used, also has a certain degree of reduction；
(5) reduce sewage discharge；Separating step of the present invention is reduced, and the first step separates the ethanol/water/Phosphoric Acid for producing
(in reactions steps 2), can be by first obtaining disodium hydrogen phosphate (can be used as industrial chemicals), Ran Houtong with ammonia neutralising phosphoric acid
Cross Distillation recovery ethanol water recycled；The phosphoric acid aqueous systems (in reactions steps 4) that second step layering is produced, first lead to Ammonia recovery
Disodium hydrogen phosphate (can be used as industrial chemicals), then recycling apply mechanically water, DMF the or DMSO/ methanol/water bodies of centrifugation
System, by rectification isolated DMF or DMSO, methanol, water, for applying mechanically, substantially solvent can recovery；
(6) purpose product purity is high, the product crude product that traditional handicraft is obtained, and needs just obtain high-quality through repeatedly refined
The product of amount, in subtractive process, yield loss is big；Present invention process flow process directly obtains the product of content >=99%, it is not necessary to essence
System, high income, and production procedure are simple, are adapted to industrialized production；Meanwhile, advantage is provided for follow-up synthesis material medicine,
Significantly reduce in follow-up cyanalation, hydrolysis two-step reaction impurity, postprocessing working procedures are greatly simplified, and crude product primary purification can
To obtain qualified Febustat crude drug.
(4) specific embodiment
The present invention is further illustrated below by the specific embodiment of embodiment form, but the interior of the present invention can not be limited
Hold, arbitrary concrete numerical value and carrier of scope described in the claims in the present invention are and can implement.
Embodiment 1
With 4-hydroxybenzonitrile and thioacetamide as initiation material, Jing sulfur acylation reactions are not separated and continue directly to thiazole
Reaction, then separate, obtain 2- (4- hydroxy phenyls) -4- methyl thiazole-5-carboxyl acid ethyl esters (formula III)：
(1) sulfur acylation reaction：With 4-hydroxybenzonitrile and thioacetamide as initiation material, sulfonyl reaction is first carried out,
In clean reaction bulb, input 70g polyphosphoric acids, 1.5g water are configured to anhydrous phosphoric acid system, and 12.7g sulfur is added in the system
For acetamide and 20g 4-hydroxybenzonitriles, stirring is warming up to 40-80 DEG C, response time 2-8 hour；Reaction is detected whether with HPLC
Completely, 4- hydroxythiobenzamides (Formula II) are obtained；
(2) thiazoleization reaction：After sulfur acylation reaction is complete, it is not necessary to separate, continue the reaction of next step thiazoleization, anti-
Organic solvent 60g ethanol is added in answering system, anhydrous phosphoric acid+alcohol system is obtained, then is slowly added dropwise 30g 2- chloroethene ethyl acetoacetic acid second
Ester, temperature control 30-80 DEG C, insulation reaction, response time are 3-6 hours, complete with HPLC detection reactions, add 60g water knot
Crystalline substance, slow cooling are filtered to 0 DEG C, are washed with a small amount of ice ethanol (10g), and wet product dries to obtain faint yellow solid 2- (4- hydroxy benzeness
Base) -4- methyl-5-thiazole formic acid ethyl ester (formula III) 38g, chromatographic purity >=99%, two step yields about 86%, content 99.5%；
With the 2- (4- hydroxy phenyls) -4- methyl thiazole-5-carboxyl acid ethyl esters (formula III) that obtains as raw material, Jing formylateds are anti-
Should, do not separate and continue directly to isobutyl reaction, then separate, obtain 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methyl thiazoliums
Azoles -5- Ethyl formates (Formulas I)：
(3) formylation reaction：In clean reaction bulb, input 170g polyphosphoric acids, 10g sulphuric acid, six methines of 22.3g
Four ammoniums, 38g 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III), stir temperature reaction, control reaction temperature
60-120 DEG C of degree, the response time is 3-10 hours, and HPLC detection reactions are complete, add 234g butyl acetates and 126g water, stir
Mix, stand, layering, organic layer add 76g water (can be used for next group to apply mechanically) stirring, stand, and layering, organic layer are concentrated to dryness
Containing 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl ester (formula IV) reaction masses；
(4) isobutyl reaction：After formylation reaction is complete, it is not necessary to separate, continue next isobutyl reaction, with
DMF adds 164g dimethylformamides, dissolving to add 14g potassium carbonate, Deca 21.7g bromo isobutyl as reaction dissolvent
Alkane, temperature reaction, controlling reaction temperature 60-115 DEG C, response time are 3-10 hours, complete to HPLC detection reactions, slow to drip
Plus 76g water, be cooled to room temperature filtration, centrifugation, centrifugal filter cake first washed once with 50g DMF (dimethylformamide), at a high speed from
The heart is dried；Then with 19g water washings for the first time, high speed centrifugation is dried, and with 19g water washings for the second time, high speed centrifugation is dried；Finally
Washed with 15g methanol for the first time, high speed centrifugation is dried, washed with 15g methanol second, high speed centrifugation is dried；Wet product is dried
2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates (Formulas I) 34.2g, chromatographic purity 99.2%, content
99.5%, two step total recoverys are 68.2%.
Embodiment 2
According to each step of embodiment 1, thiazoleization reaction does reaction dissolvent with anhydrous phosphoric acid, methanol, and remaining process is same
Embodiment 1, obtains white solid 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates (Formulas I) 30.1g,
HPLC contents 99.2%, yield 51.6%.
Embodiment 3
According to each step of embodiment 1, formylation reaction does reaction dissolvent with polyphosphoric acids, phosphoric acid, and extractant is
Ethyl acetate, remaining process obtain white solid 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazol -5- with embodiment 1
Ethyl formate (Formulas I) 28.9g, HPLC contents 99.12%, yield 49.6%.
Embodiment 4
According to each step of embodiment 1, using dimethyl sulfoxide (DMSO) as solvent, sodium carbonate is made for isobutyl reaction
For nertralizer, remaining process obtains white solid 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazol -5- with embodiment 1
Ethyl formate (Formulas I) 30.61g, HPLC contents 98.8%, yield 52.6%.
Claims (7)
1. a kind of synthetic method of highly purified 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates,
It is characterized in that methods described is with 4-hydroxybenzonitrile and thioacetamide as initiation material, Jing sulfur acylation reactions obtain formula (II) chemical combination
Thing, product do not separate direct thiazoleization reaction, isolated formula (III) thiazole derivant；Again by isolated formula
(III) compound Jing formylation reactions obtain formula (IV) compound, and product does not separate direct isobutyl reaction, obtains formula
(I) 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylate products, purity >=99%, content >=
99%, specifically include following steps：
(1) sulfur acylation reaction：With cyanophenol as initiation material, sulfur acylation reaction is carried out with thioacetamide, in anhydrous phosphoric acid
React in system, reaction temperature 40-80 DEG C, response time 2-8 hour, the anti-of hydroxythiobenzamide containing 4- (Formula II) is obtained
Answer product, wherein thioacetamide：The mol ratio of 4-hydroxybenzonitrile is 1.1～4.2：1；Anhydrous phosphoric acid system is with polyphosphoric acids
Add water and be configured to, wherein polyphosphoric acids：The weight ratio of water is 20：1～2；
(2) thiazoleization reaction：The above-mentioned product containing 4- hydroxythiobenzamides, separates without product, directly
Add organic solvent alcohols diluting reaction system, polyphosphoric acids：Organic solvent alcohols：The weight ratio of 4-hydroxybenzonitrile is 2～8：2
～7.5：1；Then Deca 2- chloroacetyl acetacetic ester carries out thiazole reaction, reaction temperature 30-80 DEG C, and the response time, 3-6 was little
When, product adds water crystallize, cooling, filters, uses ice ethanol rinse, obtain 2- (4- hydroxy phenyls) -4- methyl-5-thiazole first
Acetoacetic ester (formula III)；Thiazole reaction directly carry out as sulfur acylation reaction is not separated, by controlling 2- chloroacetyl acetacetic esters
Inventory, 2- chloroacetyl acetacetic esters are determined with the mol ratio of initial substance：The mol ratio of 4-hydroxybenzonitrile is 1.1～3.5：
1；
(3) formylation reaction：With polyphosphoric acids plus sulphuric acid or phosphoric acid as reaction dissolvent, add six times in reaction dissolvent system
Tetramine, and intermediate 2- (4- the hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl ester (formulas that step (2) is isolated
III), formylation reaction is carried out, reaction temperature 60-120 DEG C, response time 3-10 hour, product water add organosilane ester
Extraction, organic layer are concentrated to dryness, obtain containing 2- (3- carboxaldehyde radicals -4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula IV)
Reaction mass, do not separate, be directly used in next step reaction；Wherein hexamethylenetetramine：(2- (4- hydroxy phenyls) -4- methyl -
5- thiazole ethyl formates) (formula III) mol ratio be 1.1～3.5：1；
(4) isobutyl reaction：Using DMF or DMSO as solvent, will be the above-mentioned reaction mass containing formula (IV) compound molten clear, plus
Enter nertralizer, then Deca isobutane bromide, carry out isobutyl reaction, response time 3-10 hour, reaction temperature 60-115 DEG C,
After reaction terminates, add water precipitation, cooling, filters, centrifugation, and rinsing obtains 2- (3- aldehyde radical -4- isobutoxy phenyls) -4- methyl
Thiazole -5- Ethyl formates (Formulas I)；As step (3) product is not separated, next step isobutyl reaction is directly carried out, because
This, controls the mol ratio of isobutane bromide and initial substance (formula III), isobutane bromide：2- (4- hydroxy phenyls) -4- methyl -
The mol ratio of 5- thiazole ethyl formates is 1.1～4.5：1.
2. synthetic method according to claim 1, it is characterised in that the formylation reaction in step (3) is in poly
Carry out in phosphoric acid+sulphuric acid or polyphosphoric acids+Phosphoric Acid, wherein polyphosphoric acids：Sulphuric acid：2- (4- hydroxy phenyls) -4- methyl -
The weight ratio of 5- thiazole ethyl formates (formula III) is 1～10：0.2～0.5：1 or polyphosphoric acids：Phosphoric acid：2- (4- hydroxy benzeness
Base) -4- methyl-5-thiazole formic acid ethyl esters (formula III) weight ratio be 1～10：0.2～0.5：1.
3. synthetic method according to claim 1, it is characterised in that the organosilane ester in step (3) be selected from butyl acetate or
One kind in ethyl acetate, wherein organosilane ester：Water：2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
Weight ratio be 3～8：2～7.5：1.
4. synthetic method according to claim 1, it is characterised in that the reaction dissolvent described in step (4) be DMF or
One kind in DMSO, wherein reaction dissolvent：The volume weight of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
Amount is than being 3～8L：1kg.
5. synthetic method according to claim 1, it is characterised in that the nertralizer described in step (4) be selected from potassium carbonate or
One kind in sodium carbonate, wherein nertralizer：The mol ratio of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III)
For 0.5～1：1.
6. synthetic method according to claim 1, it is characterised in that the product described in step (4) adds water precipitation mesh
Product, wherein water：The weight ratio of 2- (4- hydroxy phenyls) -4- methyl-5-thiazole formic acid ethyl esters (formula III) is 2～4：1.
7. synthetic method according to claim 1, it is characterised in that the rinsing process described in step (4) be with DMF,
Water, methanol rinse, are first rinsed once with organic solvent DMF, then are rinsed twice with water, are finally rinsed twice with methanol solvate.
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