CN105085469A - Preparation method of 5-chlorothienyl-2-carboxylic acid - Google Patents
Preparation method of 5-chlorothienyl-2-carboxylic acid Download PDFInfo
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- CN105085469A CN105085469A CN201510576338.6A CN201510576338A CN105085469A CN 105085469 A CN105085469 A CN 105085469A CN 201510576338 A CN201510576338 A CN 201510576338A CN 105085469 A CN105085469 A CN 105085469A
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- carboxylic acid
- chlorothiophene
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000002994 raw material Substances 0.000 claims abstract description 16
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 111
- 239000007864 aqueous solution Substances 0.000 claims description 33
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 claims description 26
- 229910019142 PO4 Inorganic materials 0.000 claims description 25
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 25
- 239000010452 phosphate Substances 0.000 claims description 25
- 229910052700 potassium Inorganic materials 0.000 claims description 25
- 239000011591 potassium Substances 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- GVVITKMOMFXUKN-UHFFFAOYSA-N 1-(3-chlorothiophen-2-yl)ethanone Chemical compound CC(=O)C=1SC=CC=1Cl GVVITKMOMFXUKN-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 239000003495 polar organic solvent Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000006174 pH buffer Substances 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- ZJIPHXXDPROMEF-UHFFFAOYSA-N dihydroxyphosphanyl dihydrogen phosphite Chemical compound OP(O)OP(O)O ZJIPHXXDPROMEF-UHFFFAOYSA-N 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- HTZGPEHWQCRXGZ-UHFFFAOYSA-N 1-(5-chlorothiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)S1 HTZGPEHWQCRXGZ-UHFFFAOYSA-N 0.000 abstract 1
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 abstract 1
- 235000019796 monopotassium phosphate Nutrition 0.000 abstract 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 abstract 1
- 229960002218 sodium chlorite Drugs 0.000 abstract 1
- 239000000047 product Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- -1 layering Substances 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 9
- 235000010262 sodium metabisulphite Nutrition 0.000 description 9
- 230000003595 spectral effect Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 2
- 0 C[C@@]1(*C1)C1NC(N)=C(C)C1 Chemical compound C[C@@]1(*C1)C1NC(N)=C(C)C1 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 description 1
- UNILRKXHTBMQEU-UHFFFAOYSA-N CC(c1ccc(C)[s]1)OC Chemical compound CC(c1ccc(C)[s]1)OC UNILRKXHTBMQEU-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000013056 hazardous product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 229950010535 razaxaban Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to the technical field of preparation of heterocyclic compounds, and particularly discloses a preparation method of 5-chlorothienyl-2-carboxylic acid. The preparation method comprises the following steps: dissolving the raw material 5-chloro-2-acetylthiophene in acetone, dropwisely adding a potassium dihydrogen phosphate water solution at 0-10 DEG C during reaction, dropwisely adding a sodium chlorite water solution during reaction, and oxidizing at 20-30 DEG C to obtain the 5-chlorothienyl-2-carboxylic acid. The method has the advantages of mild operating conditions, high controllability, short reaction steps, high yield and no pollution, and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparing technical field of heterogeneous ring compound.
Background technology
5-chlorothiophene-2-carboxylic acid (formula
) be important intermediate for the synthesis of medicine razaxaban.
Its existing preparation method has electrochemical synthesis, biological synthesis process and chemical synthesis, and wherein electrochemical synthesis is difficult to realize large-scale industrialization; Biological fermentation process is subject to the impact of external environment and the purity of product is low, limits suitability for industrialized production.
What existing chemical synthesis was more is adopt the chloro-2-acetyl thiophene of 5-(formula
) be raw material, obtain target product by hypochlorite oxidation.
Easily decompose under the clorox high temperature that the method uses, and the impurity easily producing upper chlorine is not easy removing.The shortcomings (FamingZhuanliShenqing, 102993164,27Mar2013) such as it is low that this method exists production efficiency, and product cost is high.
PCTInt.Appl., 2011076679,30Jun2011 report adopts 2-chlorothiophene to be raw material, and tetrahydrofuran (THF) makes solvent, with carbon dioxide reaction under n-Butyl Lithium effect, more acidified 5-chlorothiophene-2-carboxylic acid, total recovery about 70%.This route relates to use hazardous material (fluids) n-Butyl Lithium, requires higher to reaction conditions, and dangerous, and yield is low, and cost is high, is not suitable for suitability for industrialized production.
ChemistryLetters, (1), 127-8; 1983 reports adopt 2-chlorothiophenes to be raw material, make catalyzer with palladium, instead give birth to react under Sodium Persulfate effect with CO (carbon monoxide converter) gas, obtain target compound 5-chlorothiophene-2-carboxylic acid, the shortcomings such as this method exists catalyzer price, and production efficiency is low, and product cost is high.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of 5-chlorothiophene-2-carboxylic acid, the inventive method operational condition is gentle, is easy to control, and reactions steps is short, product can be obtained by single step reaction, yield is high, and purity is high, and the cycle is short, cost is low, safety non-pollution, production efficiency is high, is suitable for suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method of 5-chlorothiophene-2-carboxylic acid, with the chloro-2-acetyl thiophene of 5-(formula
) be raw material, be dissolved in non-polar organic solvent, add pH buffer reagent, control reaction system pH 4 ~ 6, in reaction system, drip the aqueous solution of Textone, by formula
compound oxidation, the completely rear reaction system of oxidizing reaction is isolated to 5-chlorothiophene-2-carboxylic acid (formula
), reaction formula is:
。
Preferably, described pH buffer reagent is potassium primary phosphate.
Preferably, the mol ratio of the consumption of potassium primary phosphate and the consumption of the chloro-2-acetyl thiophene of 5-is 1 ~ 3:1.
Preferably, described non-polar organic solvent is acetone.
Preferably, the mol ratio of the consumption of Textone and the consumption of the chloro-2-acetyl thiophene of 5-is 2 ~ 4:1.
Further, at 0 ~ 10 DEG C, add the aqueous solution of potassium primary phosphate; Formula
compound oxidation temperature of reaction controls at 20 ~ 30 DEG C.
The beneficial effect adopting technique scheme to produce is:
The inventive method operational condition is easy to control, and reactions steps is short, and can obtain product by single step reaction, yield is high, and purity is high, and the cycle is short, and cost is low, safety non-pollution, and production efficiency is high, is suitable for suitability for industrialized production.
Embodiment
The present invention with the chloro-2-acetyl thiophene of 5-for raw material; after dissolving with non-polar organic solvent; buffered soln is added in 0 ~ 10 DEG C of downhill reaction system; controlling reaction system pH is 4 ~ 6; the aqueous solution of Textone is dripped again in reaction system; at 20 ~ 30 DEG C, oxidation obtains 5-chlorothiophene-2-carboxylic acid.
Conventional non-polar organic solvent all can use as chloroform, phenyl ethyl ether etc., preferably adopts acetone.
Solvable pH buffer reagent is added in reaction system, or compatible buffered soln, controlling reaction system pH is 4 ~ 6, preferably, selects the buffered soln of potassium primary phosphate.
The present invention will be further described in citing below.
Embodiment 1
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.1mol is instilled in reaction flask, the aqueous solution (13.7g potassium primary phosphate is dissolved in 25g water) 1eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (18.1g Textone is dissolved in 40g water) of Textone (0.2mol, 2eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 20g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 68.7%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 98.2%.
Embodiment 2
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.2mol is instilled in reaction flask, the aqueous solution (27.4g potassium primary phosphate is dissolved in 50g water) 2eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (18.1g Textone is dissolved in 40g water) of Textone (0.2mol, 2eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 20g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 82.5%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 99.2%.
Embodiment 3
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.3mol is instilled in reaction flask, the aqueous solution (41.1g potassium primary phosphate is dissolved in 75g water) 3eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (18.1g Textone is dissolved in 40g water) of Textone (0.2mol, 2eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 20g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 82.3%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 98.9%.
Embodiment 4
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.1mol is instilled in reaction flask, the aqueous solution (13.7g potassium primary phosphate is dissolved in 25g water) 1eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (27.2g Textone is dissolved in 60g water) of Textone (0.3mol, 3eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 30g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 69.1%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 98.5%.
Embodiment 5
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.2mol is instilled in reaction flask, the aqueous solution (27.4g potassium primary phosphate is dissolved in 50g water) 2eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (27.2g Textone is dissolved in 60g water) of Textone (0.3mol, 3eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 30g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 84.8%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 99.4%.
Embodiment 6
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.3mol is instilled in reaction flask, the aqueous solution (41.1g potassium primary phosphate is dissolved in 75g water) 3eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (27.2g Textone is dissolved in 60g water) of Textone (0.3mol, 3eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 30g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 84.9%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 99.4%.
Embodiment 7
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.1mol is instilled in reaction flask, the aqueous solution (13.7g potassium primary phosphate is dissolved in 25g water) 1eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (36.2g Textone is dissolved in 80g water) of Textone (0.4mol, 4eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 40g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 68.8%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 98.4%.
Embodiment 8
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.2mol is instilled in reaction flask, the aqueous solution (27.4g potassium primary phosphate is dissolved in 50g water) 2eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (36.2g Textone is dissolved in 80g water) of Textone (0.4mol, 4eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 40g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 84.6%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 99.5%.
Embodiment 9
Acetone 80mL is added in 500mL round bottom four-hole bottle, add 16g(0.1mol again) raw material, until system molten clear after, system is cooled to 0 ~ 10 DEG C, temperature control 0 ~ 10 DEG C, potassium primary phosphate (0.3mol is instilled in reaction flask, the aqueous solution (41.1g potassium primary phosphate is dissolved in 75g water) 3eq), drips after finishing, continues temperature control 0 ~ 10 DEG C, the aqueous solution (36.2g Textone is dissolved in 80g water) of Textone (0.4mol, 4eq) is dripped again in system.Drip after finishing, be incubated 0 ~ 10 DEG C of reaction 2 hours, system is warming up to 20 ~ 30 DEG C of reactions and detects after 20 hours.After completion of the reaction, in system, drip the aqueous solution of the Sodium Pyrosulfite of 40g20%, drip after finishing, in system, add 100mL ethyl acetate, stir suction filtration after 10 minutes, filter cake 30mL ethyl acetate drip washing, layering after merging filtrate.Aqueous phase with 50mL extraction into ethyl acetate once.Combined ethyl acetate phase, washes once with 50mL saturated sodium-chloride water solution, layering, and organic phase is concentrated obtains product 5-chlorothiophene-2-carboxylic acid, and yield is 84.8%.Fusing point: 150 ~ 152 DEG C.High-efficient liquid phase color spectral purity is 99.3%.
Claims (7)
1. a preparation method for 5-chlorothiophene-2-carboxylic acid, is characterized in that, with the chloro-2-acetyl thiophene of 5-(formula
) be raw material, be dissolved in non-polar organic solvent, add pH buffer reagent, control reaction system pH 4 ~ 6, in reaction system, drip the aqueous solution of Textone, by formula
compound oxidation, the completely rear reaction system of oxidizing reaction is isolated to 5-chlorothiophene-2-carboxylic acid (formula
), reaction formula is:
。
2. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 1, is characterized in that described pH buffer reagent is potassium primary phosphate.
3. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 2, is characterized in that the mol ratio of the consumption of potassium primary phosphate and the consumption of the chloro-2-acetyl thiophene of 5-is 1 ~ 3:1.
4. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 1, is characterized in that described non-polar organic solvent is acetone.
5. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 1, is characterized in that the mol ratio of the consumption of Textone and the consumption of the chloro-2-acetyl thiophene of 5-is 2 ~ 4:1.
6. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 2, is characterized in that, add the aqueous solution of potassium primary phosphate at 0 ~ 10 DEG C; Formula
compound oxidation temperature of reaction controls at 20 ~ 30 DEG C.
7. the preparation method of a kind of 5-chlorothiophene-2-carboxylic acid according to claim 1, is characterized in that, formula
compound from the separation method reaction system is: after completion of the reaction, adds the aqueous solution of pyrophosphorous acid sodium, re-use extraction into ethyl acetate in reaction system, gained organic phase through saturated common salt water washing, concentrated obtain product 5-chlorothiophene-2-carboxylic acid.
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| CN115403555A (en) * | 2021-05-26 | 2022-11-29 | 上海茂晟康慧科技有限公司 | Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
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| CN115403555A (en) * | 2021-05-26 | 2022-11-29 | 上海茂晟康慧科技有限公司 | Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
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