CN108840854A - A kind of method of one pot process 5- chlorothiophene -2- carboxylic acid - Google Patents
A kind of method of one pot process 5- chlorothiophene -2- carboxylic acid Download PDFInfo
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- CN108840854A CN108840854A CN201811089265.8A CN201811089265A CN108840854A CN 108840854 A CN108840854 A CN 108840854A CN 201811089265 A CN201811089265 A CN 201811089265A CN 108840854 A CN108840854 A CN 108840854A
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- 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
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Abstract
The present invention relates to a kind of methods of one pot process 5- chlorothiophene -2- carboxylic acid, and chlorinating agent is passed through or is added in 2 thiophene carboxaldehyde, insulation reaction, after the reaction was completed up to the chloro- 2 thiophene carboxaldehyde of intermediate 5-, are directly used in react in next step without isolation；The above-mentioned chloro- 2 thiophene carboxaldehyde of intermediate 5- is slowly dropped into the liquid alkaline of pre-cooling, and reaction temperature is controlled no more than 30 DEG C, cool down after being added dropwise, be slowly introducing chlorine, leads to complete insulation reaction, middle control is cooled to 5 DEG C after completion of the reaction, sodium sulfite is added to be quenched, solvent extraction removal of impurities is added, water phase adjusts pH with concentrated hydrochloric acid, it filters, filter cake recrystallization is dried to obtain target compound.The present invention solves prior art raw material high price, cumbersome, more than the three wastes disadvantage, provides a kind of method of synthesis 5- chlorothiophene -2- carboxylic acid of suitable industrialized production.
Description
Technical field
The present invention relates to technical field of organic synthesis, especially a kind of method of one pot process 5- chlorothiophene -2- carboxylic acid.
Background technique
Razaxaban is a kind of efficient novel anticoagulant researched and developed jointly by Beyer Co., Ltd and Johson & Johnson.It can be high
Degree selectively directly inhibits to be in free or bonding state Xa factor, generates anticoagulation, has bioavilability high, treats
Spectrum of disease is wide, and dose-effect relationship is stablized, convenient oral, the low feature of bleeding risk.
5- chlorothiophene -2- carboxylic acid is a kind of important intermediate for synthesizing razaxaban, there is its preparation of document report at present
Method, it is specific as follows：
(1) using 2- chlorothiophene as the preparation method of raw material
A kind of synthetic method of 5- chlorothiophene -2- carboxylic acid of document report：Using lithium diisopropylamine (LDA) as by force
Alkali, anhydrous tetrahydro furan are passed through the slotting carbonyl of atmospheric carbon dioxide at low temperature and obtain product as solvent.The route is related to anhydrous nothing
Oxygen operation, larger to equipment requirement, wherein LDA is combustibles, and operational risk is big；Tetrahydrofuran is using preceding needing to carry out anhydrous place
Reason, the long peroxide easily generated of storage time, there are larger security risks；In addition to this, 2- chlorothiophene is on the high side, reacts and receives
The more low factors of rate limit its industrialized production [RSC Advance, 2014, vol.4, #26, p.13430-13433].
Patent CN106146457 is disclosed：Using 2- chlorothiophene as initial feed, with trichloro-acetic chloride under alchlor effect
It carries out friedel-crafts acylation and generates 2- trichloroacetyl -5- chlorothiophene, then hydrolyze to obtain target product through liquid alkaline.The route is being handled
The more three wastes are generated in the process, while raw material trichloro-acetic chloride is on the high side, also its industrialized production is caused to limit.
(2) using the chloro- 5- bromothiophene of 2- as the preparation method of raw material
Patent CN106518840 is disclosed：The chloro- 2- bromothiophene of 5- reacted with magnesium generate grignard reagent after be passed through carbon dioxide insert
Carbonyl carries out soda acid later and handles to obtain product.Same problems faced is that raw materials used price is higher, when preparing grignard reagent
Waterless operation is needed, industrialized production is unfavorable for.
(3) using the chloro- 2- acetyl thiophene of 5- as the preparation method of raw material
Document report：The chloro- 2- acetyl thiophene of 5- is raw material sodium chlorite, potassium dihydrogen phosphate system is aoxidized, and is obtained
To target compound.The chloro- more difficult preparation of 2- acetyl thiophene of raw material 5- used is needed with the route, price is higher, simultaneously should
Oxidation system wastewater flow rate is big, and has chlorine and have an impact process safety [Journal of American Chemical
Society,1947,vol.69,p.3096]。
Described in summary：Existing route is mostly using 2- chlorothiophene as raw material, due to being difficult to avoid in 2- chlorothiophene production process
The generation of isomers and more chloro by-products can all carry out acylation in next step or the reaction of slotting carbonyl, generate corresponding impurity, cause product
Isolate and purify difficulty；On the other hand the content that improve 2- chlorothiophene will be within other impurities control to 0.2%, it is also desirable to carry out
Distillation operation, the rate of recovery is low, cost is very high；Also generally existing three-protection design is difficult, process risk is high for other oxidation technologies, receives
The problems such as rate is low.
Summary of the invention
The invention solves above-mentioned prior art raw material high prices, cumbersome, more than the three wastes disadvantage, provide suitable industrialization
A kind of method of synthesis 5- chlorothiophene -2- carboxylic acid of production.
The technical scheme adopted by the invention to solve the technical problem：
Using 2 thiophene carboxaldehyde as initial feed, by chloro, aoxidizes one pot of two step and prepare target compound.
This method includes following technique：
Chlorinating agent is passed through or is added in 2 thiophene carboxaldehyde (I), insulation reaction, after the reaction was completed up to intermediate 5-
Chloro- 2 thiophene carboxaldehyde (II) is directly used in reacts in next step without isolation.
Above-mentioned II is slowly dropped into the sodium hydroxide solution (liquid alkaline) of pre-cooling, and controls reaction temperature and is no more than 30 DEG C,
Cool down after being added dropwise, be slowly introducing chlorine, lead to complete insulation reaction, middle control is cooled to 5 DEG C after completion of the reaction, sodium sulfite is added
It is quenched, solvent extraction removal of impurities is added, water phase adjusts pH with concentrated hydrochloric acid, filters, and filter cake recrystallization is dried to obtain target compound.
In the preparation of above-mentioned intermediate II, chlorinating agent is selected from chlorine, sulfonic acid chloride, N- chlorosuccinimide, dichloro sea
Cause, trichloroisocyanuric acid, preferably chlorine, sulfonic acid chloride.In the preparation of above-mentioned intermediate II, mole of chlorinating agent and raw material I
Than being 4:1~0.9:1, preferably 1.5:1~1.05:1.Insulation reaction temperature is -10~30 DEG C, preferably -5~25 DEG C.It protects
The warm time is 1~20 hour, preferably 1~3 hour.
In the preparation of above-mentioned target compound III, the molar ratio of liquid alkaline and intermediate II is 4:1~1:1, preferably 3.5:1
~2.2:1.The molar ratio of chlorine and intermediate II is 3:1~0.9:1, preferably 1.5:~0.95:1.
In the preparation of above-mentioned target compound III, removal of impurities be added is selected from chloroform, methylene chloride, two chloroethenes with organic solvent
Alkane, isopropyl acetate, ethyl acetate, toluene, chlorobenzene, dimethylbenzene, preferably methylene chloride, isopropyl acetate.Above-mentioned targeted
Close object III preparation in, II instill liquid alkaline when liquid alkaline temperature be selected from -5~40 DEG C, preferably 15~30 DEG C.Reaction temperature is selected from
60~10 DEG C, preferably 30~15 DEG C.Adjusting pH is 1~6, preferably 1~2.The ratio of ethyl alcohol and water is 10 in recrystallisation solvent:
1~2:1, preferably 5:1~2:1.
Invention has the advantages that：One, cheap 2 thiophene carboxaldehyde is used to replace the 2- chlorine of prevailing technology by raw material
Thiophene greatly reduces production cost；Two, it is directly used in next step, is not required to after the chloro- 2 thiophene carboxaldehyde of intermediate 5- (II) preparation
Any purifying is wanted, and first step reaction 2 thiophene carboxaldehyde can be used as solvent, not need that solvent additionally is added, production capacity obtains larger
The promotion of degree；Three, oxidation reaction, which uses, is prepared in situ sodium hypochlorite as oxidant, greatly reduces the amount of waste water.In synthesis
Factor is stated, which has good prospect for industrial applications.
Specific embodiment
Embodiment 1：
2.8kg (25mol) 2 thiophene carboxaldehyde is added in 10L round bottom four-hole bottle, is cooled to -5 DEG C under mechanical stirring, slowly
It is passed through 1.8kg (25mol) chlorine, keeps Nei Wen -5~0 DEG C, leads to about 3 hours chlorine time, keeps Nei Wen -5~0 after leading to chlorine
The reaction was continued at DEG C 2 hours, and TLC shows raw material fully reacting, and GC shows the 85% chloro- 2 thiophene carboxaldehyde of title intermediate 5-.
Keep above-mentioned reaction solution being slowly dropped at Nei Wen -5~0 DEG C 5 DEG C of 20% sodium hydroxide solution of 11kg (55mol)
In, time for adding 2 hours, 15~30 DEG C of temperature are controlled, 1.8kg (25mol) chlorine is slowly introducing after being added dropwise, controls temperature
15~30 DEG C, lead to 4 hours chlorine time, the reaction was continued 4 hours at 15~30 DEG C of temperature in holding after logical chlorine, and TLC shows raw material
It disappears, HPLC displaying target product 5- chlorothiophene -2- carboxylic acid purity is 92%.Stop reaction, be cooled to 5~10 DEG C, is added
It is non-discolouring that 10% sodium sulfite aqueous solution is quenched to starch potassium iodide paper, and 5kg methylene chloride is added, quiet after stirring 30 minutes
It sets, liquid separation, gained organic layer barrelling waits applying, and 3.65kg (30mol) 30% hydrochloric acid is added dropwise into water layer, pH to 1~2 is adjusted,
A large amount of white solids are precipitated, and filter, filter cake weight in wet base 3.6kg, liquid phase purity 96%, and filter cake is transferred in 20L round bottom four-hole bottle, adds
Enter 10.8kg ethyl alcohol, 3.6kg water is warming up to reflux, and system is entirely molten, continues heat preservation 1 hour, continues to drop after being naturally cooling to 30 degree
Temperature filters, filter cake 500g ethanol/water (ethyl alcohol to 10 degree：Water=3:1) it elutes one time, is dried under reduced pressure to obtain 3.1kg target product
5- chlorothiophene -2- carboxylic acid, liquid phase purity 98.8%.
Embodiment 2：
2.8kg (25mol) 2 thiophene carboxaldehyde is added in 10L round bottom four-hole bottle, is cooled to -5 DEG C under mechanical stirring, slowly
1.7kg (13mol) sulfonic acid chloride is added dropwise, keeps Nei Wen -5~0 DEG C, time for adding 2 hours, Nei Wen -5~0 being kept after completion of dropwise addition
The reaction was continued at DEG C 2 hours, and TLC shows raw material fully reacting, and GC shows the 83% chloro- 2 thiophene carboxaldehyde of title intermediate 5-.
Keep above-mentioned reaction solution being slowly dropped at Nei Wen -5~0 DEG C 5 DEG C of 20% sodium hydroxide solution of 11kg (55mol)
In, time for adding 2 hours, 15~30 DEG C of temperature are controlled, continues to be cooled to -5~0 DEG C after being added dropwise, is slowly introducing 1.8kg
(25mol) chlorine leads to 4 hours chlorine time, and the reaction was continued 4 hours at 15~30 DEG C of temperature in holding after logical chlorine, TLC display original
Material disappears, and HPLC displaying target product 5- chlorothiophene -2- carboxylic acid purity is 91%.Stop reaction, be cooled to 5~10 DEG C, is added
It is non-discolouring that 10% sodium sulfite aqueous solution is quenched to starch potassium iodide paper, and 5kg methylene chloride is added, quiet after stirring 30 minutes
It sets, liquid separation, gained organic layer barrelling waits applying, and 3.6kg (30mol) 30% hydrochloric acid is added dropwise into water layer, adjusts pH to 1~2, greatly
It measures white solid to be precipitated, filter, filter cake weight in wet base 3.6kg, liquid phase purity 96%, filter cake is transferred in 20L round bottom four-hole bottle, is added
10.8kg ethyl alcohol, 3.6kg water are warming up to reflux, and system is entirely molten, continue heat preservation 1 hour, continue to cool down after being naturally cooling to 30 degree
To 10 degree, filter, filter cake 500g ethanol/water (ethyl alcohol：Water=3:1) it elutes one time, is dried under reduced pressure to obtain 3.0kg target product 5-
Chlorothiophene -2- carboxylic acid, liquid phase purity 97.7%.
In addition to the implementation, the present invention can also have other embodiments.It is all to use equivalent substitution or equivalent transformation shape
At technical solution, fall within the scope of protection required by the present invention.
Claims (6)
1. a kind of method of one pot process 5- chlorothiophene -2- carboxylic acid, includes the following steps：
1) chlorinating agent is passed through or is added in 2 thiophene carboxaldehyde, insulation reaction, after the reaction was completed up to the chloro- 2- thiophene of intermediate 5-
Pheno formaldehyde is directly used in reacts in next step without isolation；
2) the above-mentioned chloro- 2 thiophene carboxaldehyde of intermediate 5- is slowly dropped into the liquid alkaline of pre-cooling, and controls reaction temperature no more than 30
DEG C, cool down after being added dropwise, be slowly introducing chlorine, lead to complete insulation reaction, middle control is cooled to 5 DEG C after completion of the reaction, sulfurous is added
Sour sodium is quenched, and solvent extraction removal of impurities is added, and water phase adjusts pH with concentrated hydrochloric acid, filters, and filter cake recrystallization is dried to obtain target chemical combination
Object.
2. the method for one pot process 5- chlorothiophene -2- carboxylic acid according to claim 1, it is characterized in that：Chlorinating agent choosing
From chlorine, sulfonic acid chloride, N- chlorosuccinimide, two chlordantoins, trichloroisocyanuric acid, preferably chlorine, sulfonic acid chloride.
3. the method for one pot process 5- chlorothiophene -2- carboxylic acid according to claim 1, it is characterized in that：It is protected in step 1)
Warm reaction temperature is -10~30 DEG C, and soaking time is 1~20 hour.
4. the method for one pot process 5- chlorothiophene -2- carboxylic acid according to claim 1, it is characterized in that：It is organic except using mixedly
Solvent is selected from chloroform, methylene chloride, dichloroethanes, isopropyl acetate, ethyl acetate, toluene, chlorobenzene, dimethylbenzene.
5. the method for one pot process 5- chlorothiophene -2- carboxylic acid according to claim 1, it is characterized in that：5- in step 2)
The temperature of liquid alkaline is selected from -5~40 DEG C when chloro- 2 thiophene carboxaldehyde instills liquid alkaline, and reaction temperature is selected from 60~10 DEG C, and adjusting pH is 1
~6.
6. the method for one pot process 5- chlorothiophene -2- carboxylic acid according to claim 1, it is characterized in that：Chlorinating agent with
The molar ratio of 2 thiophene carboxaldehyde is 4:1~0.9:1, the molar ratio of liquid alkaline and the chloro- 2 thiophene carboxaldehyde of 5- is 4:1~1:1, chlorine with
The molar ratio of the chloro- 2 thiophene carboxaldehyde of 5- is 3:1~0.9:1.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN111072628A (en) * | 2019-12-30 | 2020-04-28 | 四川伊诺达博医药科技有限公司 | Method for synthesizing 2-acetyl-4-chlorothiophene |
| 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 |
| 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 |
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| JP2009221109A (en) * | 2008-03-13 | 2009-10-01 | Konica Minolta Holdings Inc | Method for producing heterocyclic 5-membered ring aldehyde compound |
| 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 |
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Patent Citations (3)
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| JP2009221109A (en) * | 2008-03-13 | 2009-10-01 | Konica Minolta Holdings Inc | Method for producing heterocyclic 5-membered ring aldehyde compound |
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110317189B (en) * | 2019-07-19 | 2020-07-28 | 安徽中羰碳一工业技术有限责任公司 | Method for synthesizing 5-chlorothiophene-2-formic acid by taking thiophene-2-formic acid as raw material |
| CN111072628A (en) * | 2019-12-30 | 2020-04-28 | 四川伊诺达博医药科技有限公司 | Method for synthesizing 2-acetyl-4-chlorothiophene |
| 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 |
| 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 |
| CN115557928B (en) * | 2022-10-25 | 2024-03-19 | 浙江燎原药业有限公司 | Synthesis method of 2-chlorothiophene-5-formic acid |
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