CN115403555A - Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid - Google Patents
Synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid Download PDFInfo
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- CN115403555A CN115403555A CN202110575874.XA CN202110575874A CN115403555A CN 115403555 A CN115403555 A CN 115403555A CN 202110575874 A CN202110575874 A CN 202110575874A CN 115403555 A CN115403555 A CN 115403555A
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- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 title claims abstract description 21
- DEXXSYVEWAYIGZ-LBPRGKRZSA-N 4-[4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one Chemical compound O=C1O[C@@H](CN)CN1C1=CC=C(N2C(COCC2)=O)C=C1 DEXXSYVEWAYIGZ-LBPRGKRZSA-N 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- 238000006170 formylation reaction Methods 0.000 claims abstract description 15
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 230000022244 formylation Effects 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 97
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 52
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 40
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 19
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000007800 oxidant agent Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 8
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 8
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 6
- 229960002218 sodium chlorite Drugs 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- 239000008096 xylene Substances 0.000 claims description 6
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 claims description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 5
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 4
- UXBLSWOMIHTQPH-UHFFFAOYSA-N 4-acetamido-TEMPO Chemical compound CC(=O)NC1CC(C)(C)N([O])C(C)(C)C1 UXBLSWOMIHTQPH-UHFFFAOYSA-N 0.000 claims description 4
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003810 Jones reagent Substances 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 45
- 230000008901 benefit Effects 0.000 abstract description 11
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002699 waste material Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 5
- 229930192474 thiophene Natural products 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 238000001514 detection method Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 229960001148 rivaroxaban Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical compound CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229950009390 symclosene Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 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
- C07D333/40—Thiophene-2-carboxylic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthetic method of a rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid (CAS: 24065-33-6) shown as a formula (d), which is characterized in that thiophene is used as a raw material, and the rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid is synthesized through three reactions of chlorination, formylation and oxidation. The synthetic method has the advantages of high yield, good stability, simple and convenient operation, less three wastes, low cost, less uncontrollable generated impurities, suitability for industrial production, remarkable economic benefit and the like.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a synthetic method of a rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid.
Background
Rivaroxaban (CAS: 366789-02-8, trade name is Bairuituo) is used as a famous novel anticoagulant drug which can be orally taken, is jointly developed by German Bayer and America, is listed in Canada and European Union in 9 and 10 months in 2008, is approved to be listed in the America in 7 months in 2011, is approved to be listed in 29 countries including China at present, and has wide market demand; and 5-chlorothiophene-2-carboxylic acid (CAS: 24065-33-6) is a key intermediate for the synthesis of rivaroxaban.
At present, in the process of synthesizing 5-chlorothiophene-2-carboxylic acid, a plurality of related patents or documents exist. Taking (CN 106146457a, RSCAdvancs2014,4 (26), 13430-13433) as an example, these routes all use 2-chlorothiophene as a starting material to synthesize 5-chlorothiophene-2-carboxylic acid, and more or less defects such as poor process stability, tedious operation, low yield, more three wastes, serious environmental pollution, uncontrollable impurity generation and the like exist, so that the production risk is high, the cost is high, and the method is not suitable for industrial production.
Specifically, the method comprises the following steps: the method described in the academic literature (RSCAdvancs 2014,4 (26), 13430-13433) is to synthesize 5-chlorothiophene-2-carboxylic acid by using a compound 2-chlorothiophene as a raw material, extracting hydrogen by using strong base, inserting carbon, and acidifying in one pot, wherein the synthetic process is shown as a route (B):
the patent document (CN 106146457 a) describes a method of using 2-chlorothiophene as a raw material, performing a friedel-crafts reaction on trichloroacetyl, and then performing hydrolysis and acidification to obtain 5-chlorothiophene-2-carboxylic acid, wherein the synthetic process is shown as a scheme (C):
the above two synthetic methods have the following obvious drawbacks: route (B): 1. LDA is used in the reaction of the step, the cost is higher, the reaction condition is harsher, no water and oxygen and low temperature are required, the reaction volume ratio is larger, and the productivity is limited; 2. the solvent used in the step can not be recycled and reused, and the amount is large, so that the treatment difficulty, treatment amount and treatment cost of three wastes are obviously increased. Route (C): in the course of Friedel-crafts reaction, aluminium trichloride is used as Lewis acid, and trichloroacetyl chloride is strong acid, its reaction selectivity is poor, several isomers can be produced, and its side reaction can not be controlled, so that it is not favourable for following treatment and purification, so that it can affect the quality of final product.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a novel industrial synthesis method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid. The synthetic method of the invention takes the compound of the formula a as a raw material, and the rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid is synthesized through chlorination, formylation and oxidation reactions in sequence. The method has the advantages of high process stability, simple operation, economy, environmental protection, suitability for industrial production and the like.
The invention provides a synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid, the synthetic process is shown as a route (A),
the invention relates to a synthetic method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid, which comprises the following specific steps:
step 1), in a first solvent, under the action of a chlorinating reagent, carrying out chlorination reaction on a compound shown in a formula a and the chlorinating reagent to obtain a compound shown in a formula b;
step 2), in a second solvent, under the action of a formylation reagent, carrying out formylation reaction on the compound of the formula b obtained in the step 1) to obtain a compound of a formula c;
and 3) carrying out oxidation reaction on the compound of the formula c obtained in the step 2) in a third solvent under the action of an oxidant to obtain a compound of a formula d.
In the step 1), the chlorinated reagent is one or more of sodium hypochlorite, sodium chlorite, NCS, hydrochloric acid, TCCA, hydrogen peroxide, chlorine, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride and the like; preferably, it is sulfonyl chloride.
In the step 1), the first solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, acetone, acetonitrile and the like; preferably, dichloromethane.
In the step 1), the molar ratio of the compound of the formula a to the chlorinated reagent is 1: (1-5); preferably, 1:1.1.
in the step 1), the volume ratio of the first solvent to the compound shown in the formula a is (1-10) to 1; preferably 5:1.
In the step 1), the temperature of the chlorination reaction is-10-60 ℃; preferably, it is 25 ℃.
In the step 1), the time of the chlorination reaction is 1-36h; preferably, it is 2h.
Step 1) is preferably carried out under nitrogen protection.
In the step 2), the second solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, xylene, tetrahydrofuran, dioxane, acetonitrile and the like; preferably, it is 1,2-dichloroethane.
In the step 2), the formylation reagent is one or more of DMF, sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride, phosphorus oxychloride, thionyl chloride and the like; preferably, the mixed system is a mixed system of DMF and oxalyl chloride, and further, the molar ratio of the DMF to the oxalyl chloride is 1:1.
In the step 2), the mole ratio of the compound of the formula b to the formylation reagent is 1: (1-10); preferably, 1:2.5.
in the step 2), the volume ratio of the second solvent to the compound of the formula b is (1-10): 1; preferably, 3:1.
in the step 2), the temperature of the formylation reaction is 0-110 ℃; preferably, it is 80 ℃.
In the step 2), the formylation reaction time is 1-24h; preferably, it is 8h.
In the step 3), the third solvent is one or more of toluene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, DMF, DMSO, water and the like; preferably, the mixed system is a mixed system of water and DMSO, and further, the volume ratio of the water to the DMSO is 1:2.
in the step 3), the oxidant is one or more of sodium hypochlorite, sodium chlorite, sodium chlorate, hydrogen peroxide, jone reagent, potassium permanganate, sodium periodate, TEMPO, 4-hydroxy-TEMPO, 4-acetamido-TEMPO and the like; preferably, sodium hypochlorite.
In the step 3), the molar ratio of the compound of the formula c to the oxidant is 1: (1-15); preferably, 1:5.
in step 3), the volume ratio of the third solvent to the compound of formula c is (1-15): 1; preferably, 9:1.
in the step 3), the temperature of the oxidation reaction is 0-100 ℃; preferably, it is 40 ℃.
In the step 3), the time of the oxidation reaction is 1-16h; preferably, it is 5h.
In the route of the invention, the reaction stability is high, the operation is simple, the three wastes are less, and the cost has obvious advantages.
The process for obtaining the compound of formula d according to the invention has the following advantages: 1) The chlorination reaction is simple to operate, the crude product obtained by concentrating after the reaction can be directly put into the next step, the yield is high (about 100 percent), the pollution is less, and the treatment cost is low; 2) The formylation reaction is simple and convenient to operate, and the obtained crude product of the compound of the formula c can be directly put into the next reaction; 3) The oxidation reaction steps are mild in condition, the yield is quite high (the total yield of the three steps is about 80 percent), and the purity is good (about 99 percent).
Compared with the existing synthetic method, the synthetic route of the rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid has the following remarkable advantages: compared with other chlorinated reagents in the prior art, the method has the advantages of simpler operation, less environmental pollution, no solid waste and lower treatment cost; in the step 2), a mixed system of oxalyl chloride, DMF and the like is used as a formylation reagent, and compared with other formylation reagents in the prior art, uncontrollable impurities such as isomers and the like are not generated, so that the subsequent purification cost is further reduced; the crude product obtained by concentrating the treated reaction solution in the step 2) can be put into the next reaction without purification, so that the production cost is further reduced; and 3) sodium hypochlorite and the like are used as oxidants, so that the method is more economical and environment-friendly compared with other oxidants in the prior art, and the product is purified by adjusting acid and alkali, so that the three-waste treatment cost is low.
In a specific embodiment, the industrial synthetic route of the rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid represented by the formula (d) is as follows:
the beneficial effects of the invention also include: the method has the advantages of high process stability, simple operation, less three wastes, high yield, less uncontrollable impurities and low production cost, is suitable for industrial mass production, and has obvious economic benefit.
Corresponding full-name corresponding table used for short names in the specification
| Entry | Abbreviations | Full scale |
| 1 | DCM | Methylene dichloride |
| 2 | TEMPO | 2,2,6,6-Tetramethylpiperidine oxide |
| 3 | TCCA | Trichloroisocyanuric acid |
| 4 | DMSO | Dimethyl sulfoxide |
| 5 | DMF | N, N-dimethylformamide |
| 6 | NCS | N-chlorosuccinimide |
| 7 | LDA | Lithium diisopropylamide |
Detailed Description
The present invention will be described in further detail with reference to the following specific examples. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Synthesis of compounds of formula b:
scheme 1:
under the protection of nitrogen, dichloromethane (150mL, 5V) and thiophene (30g, 356.55mmol) are added into a 250mL reaction kettle, sulfonyl chloride (50.53g, 374.38mmol) is added dropwise at 0 ℃, and after the addition is finished, the reaction is carried out for 2 hours at 25 ℃, and the detection is carried out by GC or TLC, so that the reaction is finished. Concentrating to obtain a crude product, and directly putting the crude product into the next reaction (putting the crude product into the next reaction according to the theoretical yield).
Crude compound of formula b: 1 H NMR(400MHz,CHLOROFORM-d)δppm 6.87(m,1H)，6.90(m,1H)，7.08(m,1H)。
according to the scheme, sulfonyl chloride is chlorinated, after the reaction is finished, the crude product obtained by direct concentration and drying is directly put into the next step, the yield is high, the operation flow is simple and convenient, the reaction safety is high, uncontrollable impurities are not generated, the generated dichloromethane can be directly applied to the next pot, and compared with the method recorded in the existing literature, the method has obvious advantages and is suitable for industrial production.
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
under the protection of nitrogen, dichloromethane (150mL, 5V) or 1,2-dichloroethane (150mL, 5V) or tetrahydrofuran (150mL, 5V) or dioxane (150mL, 5V) or acetone (150mL, 5V) or acetonitrile (150mL, 5V), thiophene (30g, 356.55mmol), sulfuryl chloride (50.53g, 374.38mmol) is added dropwise at 0 ℃, the reaction is completed after the addition, the reaction is carried out at 25 ℃ for 2 hours, and the reaction is detected by GC or TLC, so that the reaction is finished. Concentrating and drying to obtain a crude product of the compound of the formula b.
A compound of formula b obtained in a dichloromethane system (42.38g, 356.55mmol); 1,2-dichloroethane system (41.98g, 354mmol); compound of formula b obtained with tetrahydrofuran system (35.57g, 300mmol); the compound of formula b obtained with dioxane system (30.48g, 257mmol); the compound of formula b obtained in the acetone system (29.65g, 250mmol); acetonitrile system (18.38g, 155mmol);
the reaction solvent identified in this scheme is therefore preferably dichloromethane.
Schemes 1-2:
under the protection of nitrogen, dichloromethane (150mL, 5V), thiophene (30g, 356.55mmol) and sulfuryl chloride (50.53g, 374.38mmol) or hydrochloric acid (37.96g, 374.38mmol)/sodium hypochlorite (278.69g, 374.38mmol) or sodium chlorite (42.32g, 374.38mmol) or NCS (49.99g, 374.38mmol) or TCCA (87g, 374.38mmol) or chlorine gas (26.58g, 374.38mmol) or phosphorus oxychloride (57.4g, 374.38mmol) or thionyl chloride (44.54g, 374.38mmol) or phosphorus trichloride (51.41g, 374.38mmol) or phosphorus pentachloride (77.96g, 374.38mmol) or triphosgene (111.1g, 374.38mmol) or oxalyl chloride (47.52g, 38mmol) are added into a 250mL reaction kettle dropwise at 0 ℃, the reaction is finished after the reaction is finished for 2 hours, and the reaction is detected by GC at 25 ℃ or GC. Concentrating and drying the organic phase obtained after the post-treatment to obtain a crude product of the compound of the formula b.
Sulfonyl chloride system (42.38g, 356.55mmol); a compound of formula b (27.93g, 235.5mmol) obtained from a hydrochloric acid/sodium hypochlorite aqueous solution system; sodium chlorite system (35.25g, 297.3 mmol); the NCS system gave a compound of formula b (41.6g, 350.8mmol); the compound of formula b obtained in the phosphorus pentachloride system (30.55g, 257.6 mmol); TCCA system (34.33g, 289.5mmol); compound of formula b (34.47g, 290.7 mmol) obtained from chlorine reagent system; a compound (24.65g, 207.9 mmol) of the formula b obtained by a phosphorus oxychloride system; compound of formula b obtained with thionyl chloride system (23.87g, 201.3mmol); a compound of formula b (22.27g, 187.8mmol) obtained by a phosphorus trichloride system; compound of formula b obtained with triphosgene system (23.87g, 201.3mmol); oxalyl chloride system (35.73g, 301.3 mmol).
The chlorinating agent identified in this scheme is therefore preferably sulphuryl chloride.
Schemes 1-3:
under the protection of nitrogen, dichloromethane (150mL, 5V), thiophene (30g, 356.55mmol) and sulfonyl chloride (50.53g, 374.38mmol) or sulfonyl chloride (45.72g, 338.72mmol) or sulfonyl chloride (57.75g, 427.86mmol) are added dropwise into a 250mL reaction kettle at 0 ℃, and after the addition is finished, the reaction is carried out for 2 hours at 25 ℃, and the reaction is detected by GC or TLC, thus finishing the reaction. Concentrating and drying to obtain a crude product of the compound of the formula b.
Sulfonyl chloride (50.53g, 374.38mmol) system to give a compound of formula b (42.38g, 356.55mmol); sulfonyl chloride (45.72g, 338.72mmol) system to give a compound of formula b (40.17g, 338.72mmol); sulfonyl chloride (57.75g, 427.86mmol) system to give a compound of formula b (42.38g, 356.55mmol).
The molar ratio chloro reagent/compound a is therefore tentatively 1.05:1.
example 2
Synthesis of compound of formula c:
scheme 1:
the crude product (42.38g, 356.55mmol) containing the compound of formula b from the previous step, 1,2-dichloroethane (127ml, 3v), DMF (65.15g, 891.38mmol) was added to a 500mL reaction vessel, oxalyl chloride (113.14g, 891.38mmol) was added dropwise at 0 deg.C, and after the addition was completed, the temperature was raised to 80 deg.C for 8 hours, and the reaction was terminated by GC or TLC detection. And (3) cooling to 30 ℃, slowly adding the mixture into water, separating, washing, drying the organic phase, and directly concentrating until the organic phase is dry to obtain the compound of the formula c, and directly putting the compound of the formula c into the next reaction (putting the compound of the formula c into the next reaction according to 100% of theoretical yield).
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
the crude product (42.38g, 356.55mmol) containing the compound of formula b in the previous step, 1,2-dichloroethane (127ml, 3v) or dichloromethane (127ml, 3v) or toluene (127ml, 3v) or xylene (127ml, 3v) or tetrahydrofuran (127ml, 3v) or dioxane (127ml, 3v) or acetonitrile (127ml, 3v), DMF (65.15g, 891.38mmol) was added to a 500mL reaction vessel, oxalyl chloride (113.14g, 891.38mmol) was added dropwise at 0 ℃, after finishing adding, the temperature was raised to 80 ℃ for 8 hours, and GC or TLC detection ended. And cooling to 30 ℃, slowly adding the mixture into water, separating, washing, drying an organic phase, and directly concentrating to dryness to obtain the compound of the formula c.
1,2-dichloroethane system (52.27g, 356.55mmol); dichloromethane system to give compound of formula c (37.54g, 256.09mmol); toluene system to give a compound of formula c (43.99g, 300.09mmol); xylene system (44.12g, 301.1mmol); a compound of formula c obtained in the tetrahydrofuran system (45.52g, 310.5 mmol), a compound of formula c obtained in the dioxane system (38.13g, 260.09mmol); acetonitrile system to give the compound of formula c (41.06g, 280.09mmol).
The reaction solvent identified in this scheme is therefore preferably 1,2-dichloroethane.
Schemes 1-2:
the crude compound of formula b (42.38g, 356.55mmol), 1,2-dichloroethane (127ml, 3v), DMF (65.15g, 891.38mmol) from the previous step was added to a 500mL reactor dropwise at 0 deg.C, oxalyl chloride (113.14g, 891.38mmol) or sulfuryl chloride (120.31g, 891.38mmol) or phosphorus trichloride (122.41g, 891.38mmol) or phosphorus pentachloride (185.62g, 891.38mmol) or triphosgene (264.52g, 891.38mmol) or phosphorus oxychloride (136.68g, 891.38mmol) or thionyl chloride (106.05g, 891.38mmol), after finishing the reaction, the temperature was raised to 80 deg.C for 8 hours, and GC or TLC detection indicated that the reaction was complete. And cooling to 30 ℃, slowly adding the mixture into water, separating, washing, drying the organic phase, and directly concentrating to dryness to obtain the compound of the formula c.
Compound of formula c (52.27g, 356.55mmol) from the DMF/oxalyl chloride system; compound of formula c (44.07g, 300.59mmol) obtained from the DMF/sulfonyl chloride system; compound of formula c (41.12g, 280.5mmol) obtained from DMF/phosphorus trichloride system; compound of formula c (36.81g, 251.1mmol) obtained from DMF/phosphorus pentachloride system; a compound of formula c obtained in the DMF/triphosgene system (30.86g, 210.5mmol), a compound of formula c obtained in the DMF/phosphorus oxychloride system (43.32g, 295.49mmol); DMF/thionyl chloride system gave compound of formula c (48.47g, 330.67mmol).
The formalizing reagent identified in this scheme is therefore preferably a DMF/oxalyl chloride mixed system.
Schemes 1-3:
the crude compound of formula b (42.38g, 356.55mmol), 1,2-dichloroethane (127ml, 3v), DMF (65.15g, 891.38mmol) from the previous step were added to a 500mL reaction vessel, oxalyl chloride (113.14g, 891.38mmol) or oxalyl chloride (90.51g, 713.1mmol) or oxalyl chloride (135.77g, 1069.65mmol) was added dropwise at 0 deg.C, and after addition, the temperature was raised to 80 deg.C for 8 hours, and GC or TLC detection indicated that the reaction was complete. And cooling to 30 ℃, slowly adding the mixture into water, separating, washing, drying the organic phase, and directly concentrating to dryness to obtain the compound of the formula c.
Oxalyl chloride (90.51g, 713.1mmol) system in the presence of unreacted starting material to give a compound of formula c (44.0 g, 300.2mmol); oxalyl chloride (113.14g, 891.38mmol) system to give a compound of formula c (52.27g, 356.55mmol); oxalyl chloride (135.77g, 1069.65mmol) to give a compound of formula c (52.27g, 356.55mmol).
The molar ratio formaldehydizing agent/compound b is therefore tentatively 2.5:1.
example 3
Synthesis of compounds of formula d:
scheme 1:
a2000 mL reaction vessel was charged with the crude compound of formula c obtained in the previous step (52.27g, 356.55mmol), water (157mL, 3V), DMSO (314mL, 6V), sodium hypochlorite (236.98g, 1782.75mmol) added in portions at 0 deg.C, after completion of the addition, the reaction was carried out at 40 deg.C for 5 hours, and HPLC or TLC detection was carried out to complete the reaction. Adjusting pH to 1 with hydrochloric acid, filtering, and drying the solid to obtain the compound (46.38g, 285.24mmol) of the formula d, wherein the total yield of the three steps is as follows: 80 percent.
1 H NMR(400MHz,d6-DMSO):13.34(br,s,1H)；7.61(d,J＝4.0Hz,1H),7.23(d,J＝4.0Hz,1H)
Meanwhile, the invention also carries out relevant optimization on the step, and the specific implementation scheme is as follows:
scheme 1-1:
a2000 mL reaction kettle is added with the crude compound (52.27g, 356.55mmol) of the formula c obtained in the previous step, water (157mL, 3V), DMSO (314mL, 6V), sodium hypochlorite (236.98g, 1782.75mmol) or sodium chlorate (189.76g, 1782.75mmol) or hydrogen peroxide (202.03g, 1782.75mmol) or Jone reagent (178.27g, 1782.75mmol) or potassium permanganate (281.66g, 1782.75mmol) or sodium periodate (381.29g, 1782.75mmol) or TEMPO (278.56g, 1782.75mmol) or 4-hydroxy-TEMPO (307.06g, 1782.75mmol) or 4-acetamido-TEMPO (380.26g, 1782.75mmol), the reaction is finished at 40 ℃ for 5 hours, and HPLC or TLC detection is finished. Adjusting the pH value to 1 with hydrochloric acid, filtering, and drying the solid to obtain the product, namely the compound shown in the formula d.
Sodium hypochlorite system to give a compound of formula d (46.38g, 285.24mmol); a compound of formula b obtained from a sodium chlorate system (42.22g, 259.7 mmol); a compound (36.77g, 226.13mmol) of the formula b obtained by a hydrogen peroxide system; compound of formula b obtained from Jone reagent system (33.44g, 205.7 mmol); a compound of formula b obtained with a potassium permanganate system (27.34g, 168.13mmol); compound of formula b (38.84g, 238.9 mmol) from sodium periodate system; the compound of formula b obtained with TEMPO system (33.97g, 208.9 mmol); compound of formula b obtained from the 4-hydroxy-TEMPO system (32.63g, 200.7 mmol); 4-acetamido-TEMPO system (30.19g, 185.7mmol).
The oxidant identified in this embodiment is therefore preferably sodium hypochlorite.
Schemes 1-2:
adding the crude compound (52.27g, 356.55mmol) of the compound of the formula c obtained in the previous step, water (157mL, 3V), DMSO (314mL, 6V), sodium hypochlorite (236.98g, 1782.75mmol) or sodium hypochlorite (142.19g, 1069.65mmol) or sodium hypochlorite (331.77g, 2495.85mmol) in batches at 0 ℃, after finishing the reaction, reacting at 40 ℃ for 5 hours, detecting by HPLC or TLC, and finishing the reaction. Adjusting the pH value to 1 with hydrochloric acid, filtering, and drying the solid to obtain the product, namely the compound shown in the formula d.
Sodium hypochlorite (142.19g, 1069.65mmol) system still has the raw material unreacted, and the compound (42.36g, 32mmol) of the formula d is obtained; sodium hypochlorite (236.98g, 1782.75mmol) system to give a compound of formula d (46.38g, 285.24mmol); sodium hypochlorite (331.77g, 2495.85mmol) system to give a compound of formula d (46.38g, 285.24mmol).
The molar ratio oxidant/compound c is therefore tentatively 5:1.
scheme 2 (RSCAdvancs 2014,4 (26), 13430-13433):
the method disclosed by the document is characterized in that 2-chlorothiophene serving as a compound is used as a raw material, hydrogen is extracted through LDA (laser direct oxidation) strong base, carbon dioxide is introduced for carbon insertion, and 5-chlorothiophene-2-carboxylic acid is synthesized by an acidification one-pot method, wherein tetrahydrofuran is used as a solvent, so that the cost is high, the yield is only 77%, the solvent cannot be recycled, and the three wastes are more, so that the method is uneconomical and environment-friendly.
The protection content of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, which is set forth in the following claims.
Claims (10)
1. A synthetic method of a rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid is characterized in that the synthetic process of the rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid is shown as the following scheme (A),
the method comprises the following specific steps:
step 1), in a first solvent, under the action of a chlorinating reagent, carrying out chlorination reaction on a compound shown in a formula a and the chlorinating reagent to obtain a compound shown in a formula b;
step 2), in a second solvent, under the action of a formylation reagent, formylating the compound of the formula b obtained in the step 1) to obtain a compound of a formula c;
and 3) carrying out oxidation reaction on the compound of the formula c obtained in the step 2) in a third solvent under the action of an oxidant to obtain a compound of a formula d.
2. The synthesis method of claim 1, wherein in step 1), the chlorinating agent is one or more of sodium hypochlorite, sodium chlorite, NCS, hydrochloric acid, TCCA, hydrogen peroxide, chlorine gas, phosphorus oxychloride, thionyl chloride, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene and oxalyl chloride; and/or the first solvent is one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, acetone and acetonitrile.
3. The synthesis process according to claim 1, wherein in step 1), the molar ratio of the compound of formula a to the chlorinating reagent is 1: (1-5); and/or the volume ratio of the first solvent to the compound of formula a is (1-10): 1.
4. the synthesis method according to claim 1, wherein in the step 1), the temperature of the chlorination reaction is-10 to 60 ℃; and/or the time of the chlorination reaction is 1-36h.
5. The synthesis method of claim 1, wherein in the step 2), the formylation reagent is one or more of DMF, sulfuryl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, oxalyl chloride, phosphorus oxychloride and thionyl chloride; and/or the second solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, xylene, tetrahydrofuran, dioxane and acetonitrile.
6. The method of claim 1, wherein in step 2), the molar ratio of the compound of formula b to the formylating agent is 1: (1-10); and/or the volume ratio of the second solvent to the compound of formula b is (1-10): 1.
7. the synthesis method of claim 1, characterized in that in the step 2), the temperature of the formylation reaction is 0-110 ℃; and/or the time of the formylation reaction is 1-24h.
8. The method of claim 1, wherein in step 3), the third solvent is one or more of toluene, xylene, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, DMF, DMSO, and water; and/or the oxidizing agent is one or more of sodium hypochlorite, sodium chlorite, sodium chlorate, hydrogen peroxide, jone reagent, potassium permanganate, sodium periodate, TEMPO, 4-hydroxy-TEMPO and 4-acetamido-TEMPO.
9. The synthesis method according to claim 1, wherein in step 3), the molar ratio of the compound of formula c to the oxidant is 1: (1-15); and/or, the volume ratio of the third solvent to the compound of formula c is (1-15): 1.
10. the method of synthesis according to claim 1, wherein in step 3), the temperature of the oxidation reaction is 0-100 ℃; and/or the time of the oxidation reaction is 1-16h.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993164A (en) * | 2012-11-19 | 2013-03-27 | 连云港宏业化工有限公司 | Preparation method for 2-chlorine-5-thiophene formic acid |
| CN103232430A (en) * | 2013-04-30 | 2013-08-07 | 威海迪素制药有限公司 | Preparation method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
| CN103275061A (en) * | 2013-06-04 | 2013-09-04 | 上海同昌生物医药科技有限公司 | Method for producing 5-chlorothiophene-2-carboxylic acid |
| CN103497172A (en) * | 2013-10-15 | 2014-01-08 | 连云港宏业化工有限公司 | Synthetic method of 2-chlorothiophene |
| CN105085469A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of 5-chlorothienyl-2-carboxylic acid |
| CN108840854A (en) * | 2018-09-18 | 2018-11-20 | 浙江扬帆新材料股份有限公司 | A kind of method of one pot process 5- chlorothiophene -2- carboxylic acid |
| CN109422720A (en) * | 2017-08-22 | 2019-03-05 | 新发药业有限公司 | A kind of inexpensive, high-purity 5- chlorothiophene -2- formyl chloride preparation method |
| CN110317189A (en) * | 2019-07-19 | 2019-10-11 | 安徽中羰碳一工业技术有限责任公司 | A method of using thiophene -2-carboxylic acid as Material synthesis 5- chlorothiophene -2- formic acid |
| CN115557928A (en) * | 2022-10-25 | 2023-01-03 | 浙江燎原药业股份有限公司 | Synthetic method of 2-chlorothiophene-5-formic acid |
-
2021
- 2021-05-26 CN CN202110575874.XA patent/CN115403555A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102993164A (en) * | 2012-11-19 | 2013-03-27 | 连云港宏业化工有限公司 | Preparation method for 2-chlorine-5-thiophene formic acid |
| CN103232430A (en) * | 2013-04-30 | 2013-08-07 | 威海迪素制药有限公司 | Preparation method of rivaroxaban intermediate 5-chlorothiophene-2-carboxylic acid |
| CN103275061A (en) * | 2013-06-04 | 2013-09-04 | 上海同昌生物医药科技有限公司 | Method for producing 5-chlorothiophene-2-carboxylic acid |
| CN103497172A (en) * | 2013-10-15 | 2014-01-08 | 连云港宏业化工有限公司 | Synthetic method of 2-chlorothiophene |
| CN105085469A (en) * | 2015-09-11 | 2015-11-25 | 沧州那瑞化学科技有限公司 | Preparation method of 5-chlorothienyl-2-carboxylic acid |
| CN109422720A (en) * | 2017-08-22 | 2019-03-05 | 新发药业有限公司 | A kind of inexpensive, high-purity 5- chlorothiophene -2- formyl chloride preparation method |
| CN108840854A (en) * | 2018-09-18 | 2018-11-20 | 浙江扬帆新材料股份有限公司 | A kind of method of one pot process 5- chlorothiophene -2- carboxylic acid |
| CN110317189A (en) * | 2019-07-19 | 2019-10-11 | 安徽中羰碳一工业技术有限责任公司 | A method of using thiophene -2-carboxylic acid as Material synthesis 5- chlorothiophene -2- formic acid |
| CN115557928A (en) * | 2022-10-25 | 2023-01-03 | 浙江燎原药业股份有限公司 | Synthetic method of 2-chlorothiophene-5-formic acid |
Non-Patent Citations (1)
| Title |
|---|
| 商业部五金交电化工局: "《化工原料商品手册》", 中国时政经济出版社, pages: 195 - 196 * |
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