CN106831702A - A kind of preparation method of the thiophenic acid of 5 substitution 2 - Google Patents
A kind of preparation method of the thiophenic acid of 5 substitution 2 Download PDFInfo
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- 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
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Abstract
The present invention relates to a kind of preparation method for synthesizing the thiophenic acid of 5 substitution 2, concretely comprise the following steps：2 halogenated thiophenes shown in formula 1 are as raw material; zeolite molecular sieve is catalyst; trichloro-acetic chloride is acylating agent; it is well mixed under the conditions of solvent-free or organic solvent, is reacted 15~72 hours at 60~130 DEG C, obtains the compound (2) shown in formula 2; the compound (2) shown in formula 2 is added into alkaline solution again and is stirred; at 70~100 DEG C, hydrolyze 3~24 hours, obtain the target compound (3) shown in formula 3.Raw material of the present invention is cheap and easy to get, easy to operate, and running cost is low, environmental protection, and each step reaction yield far above existing synthetic route yield, industrialized production is quite suitable for, with extremely strong industrial application value.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, and in particular to a kind of 5- replaces the preparation side of -2- thiophenic acids
Method.
Background technology
Razaxaban (Rivaroxaban) is by Bayer Bitterfeld GmbH medicine and Johnson Co.'s cooperative research and development success.2008
In October, got the Green Light listing, trade name Xarelto in Canada and European Union.Razaxaban is oral straight first, the whole world
Connect Xa factor inhibitor, can high selectivity, Reverse transcriptase be free and the Xa factor that combines and prothrombin activity, with agent
Amount-dependence mode extends activated partial thromboplastin time plate (PT) and prothrombin time (aPTT), so that when extending blood coagulation
Between, reduce fibrin ferment and formed.It has bioavilability high, and treatment spectrum of disease is wide, dose-effect relationship stabilization, convenient oral, bleeding
The characteristics of risk is low.
Razaxaban is also the medicine for preventing and treating phlebothrombosis.Clinically it is mainly used in preventing hip joint and knee replacements
The formation of patient's DVT (DVT) and pulmonary embolism (PE) afterwards.Can also be used for prevention non-valve artrial fibrillation patient brain finally
Non- central nervous system embolism is neutralized, risk of coronary syndrome recurrence etc. is reduced.Therefore the medicine prospect is extremely wide
It is wealthy.
5- substitution -2- thiophenic acids are a kind of important medicine intermediate and industrial chemicals, wherein 5- chlor-2-thiophenecar-boxylic acids
It is the key intermediate for synthesizing antithrombotic reagent Li Fashaban (Rivaroxaban).Develop the intermediate have it is wide
Market prospects.Report that in the prior art, preparing the synthetic route of 5- chlor-2-thiophenecar-boxylic acids mainly has as follows according to documents and materials
Three：
Route one：
This route needs deep cooling to react, and needs to use flammability hazard chemicals n-BuLi, to transport and storage band
It is inconvenient to come, and industrial process operation security is low, and use cost is higher, has limited to industrialized production.
Route two：
This route raw material are all easy to get, but formylation reaction is directed to use with meeting the POCl3 that water easily explodes,
Reaction is needed to carry out under the high temperature conditions, and product color is profound, and very big difficulty is brought to production post processing, and workshop is not
It is easy to operate, while nitrogenous, phosphorus waste water can be produced, strong influence is brought to environmental protection.
This route also has several replacement routes of other oxidation reactions, replaces double using natrium nitrosum or sodium hypochlorite
The scheme of oxygen water, be present same.
Route three：
This route, acylation reaction used catalyst phosphoric acid is easily polymerized coking, reduces reactivity, and acylation reaction is converted not
Completely, it is necessary to constantly add phosphoric acid, cause to darken, post processing is difficult, post processing needs to use substantial amounts of buck to process, and increases
Add substantial amounts of phosphorus-containing wastewater, it is difficult to process, pressure has been brought to environmental protection, pollute environment.Oxidation reaction uses substantial amounts of hypochlorous acid
Sodium makees oxidant, and control is improper to be also easy to produce aldehydic acid impurity, is difficult to remove, and causes yield relatively low, content reduction.While sodium hypochlorite
Extremely unstable, content reduction causes every batch of inventory to be required for increasing inventory, causes cost to increase, and to transport and storage band
Carry out very big difficulty, while producing substantial amounts of high-salt wastewater, influence is brought to environmental protection, be not suitable for industrial mass production.
The content of the invention
For the problem that prior art is present, it is easy to raw material it is an object of the invention to provide one kind and is easy to get, simple to operate,
Environmental protection, the 5- substituted thiophene formic acid preparation methods that yield is higher and implementation cost is relatively low.
To reach above-mentioned purpose, this invention takes following technical scheme：
A kind of preparation method of 5- substitutions -2- thiophenic acids, methods described is specifically carried out as follows：
(1) as raw material, zeolite molecular sieve is catalyst to the 2- halogenated thiophenes shown in formula 1, and trichloro-acetic chloride is acylating agent,
It is well mixed under the conditions of solvent-free or organic solvent, is reacted 15~72 hours at 60~130 DEG C, after reaction terminates, reaction
The post-treated compound (2) obtained shown in formula 2 of product；The amount of the material of 2- halogenated thiophenes and acylating agent shown in the formula 1
The ratio between be 1:1~2；
(2) compound (2) shown in formula 2 is added to alkaline solution and is stirred, at 70~100 DEG C, hydrolysis 3~
24 hours, after reaction terminates, the post-treated target compound (1) obtained shown in formula 1 of product；Change shown in the formula 2
The amount of the material of alkali is 1 in compound (2) and alkaline matter:1.5~3.
Wherein, the X in formula 1, formula 3 is Cl, Br or I.
Further, in the step (1), the catalyst be HY zeolites, HZSM-5 zeolites, H types silk zeolite, H- β zeolites,
Aluminium phosphate molecular sieve or aluminium silicophosphate molecular sieve, preferably HZSM-5 zeolites.
Further, in step (1), the catalyst charge is calculated as 0.1 with the 2- halogenated thiophene quality shown in formula 1~
0.5g/g。
Further, in step (1), the ratio between amount of material of preferably described 2- halogenated thiophenes and acylating agent is 1：1.2.
Further, in step (1), the organic solvent is chloroform or dichloroethanes.
Further, in step (1), the addition of organic solvent is with the 2- halogenated thiophenes shown in formula 1 in the step (1)
It is calculated as 0~5mL/g.
Further, in step (1), preferably described solvent adding conditional is solvent-free addition.
Further, in step (1), the post-processing approach of the product is：After question response terminates, by product
Room temperature is cooled to, through filtering, the recyclable catalyst of filter residue for obtaining, the excessive trichloro-acetic chloride of filtrate decompression concentration and recovery is remained
Remaining residual night is compound (2) crude product shown in formula 2.
Further, in step (2), the alkaline matter is NaOH or potassium hydroxide, preferably NaOH.
Further, in step (2), alkaline solution is the aqueous solution of alkali mass concentration 5~50%.
Further, in step (2), the post-processing approach of the product is：It is after reaction terminates, product is cold
But to 20~25 DEG C, acid adding regulation pH value is 1~3, and through cooling, filtering, frozen water drip washing is drained, heated-air circulation oven 70~80
DEG C baking material 6~8 hours, obtains target product.
Further, in step (2), regulation pH value institute acid adding is hydrochloric acid or sulfuric acid, preferably hydrochloric acid.
Compared with prior art, the beneficial effects are mainly as follows：
(1) supplementary material needed for is the industrial chemicals of commercially available simple cheap, and buying cost is low；
(2) impurity content is reduced, quality is improved, the refined number of times of finished product is reduced, yield is improve；
(3) operating difficulties present in prior art is overcome, Workshop Production is dangerous, conversion ratio is relatively low, post processing purification
Difficult defect；
(4) intermediate treatment process is reduced, production cost is reduced, the three wastes is few, catalyst recovery, reactivation repeats to make
With, reduce environmental pollution, mitigate environmental protection pressure it is big the shortcomings of, industrialized production is advantageously implemented, with extremely strong commercial Application
Value.
Specific embodiment
Embodiments of the present invention are elaborated below with reference to embodiment.Embodiments of the present invention include but not
Following embodiments are confined to, it is not construed as limiting the scope of the invention.
The 5- chlor-2-thiophenecar-boxylic acids of embodiment 1
(1) 2- chlorothiophenes 30g (0.253mol), HZSM-5 zeolite molecular sieve 3g, trichloro-acetic chloride are put into flask
45.8g (0.253mol, 1ep), heats up 130 DEG C, insulation reaction 48 hours, vapor detection control terminal, and 2- chlorothiophenes content≤
2%, terminating reaction.Cooling down to room temperature, filtering is reclaimed catalyst and is applied mechanically, three excessive chloroethenes of filtrate decompression concentration and recovery
Acyl chlorides, remaining residual night is compound (2) crude product, and weight is 63g, and yield is more than 95%, crude product it is not purified can directly under
Single step reaction.
(2) compound (2) 65.5g (0.248mol), 5% sodium hydroxide solution 300g are put into reaction bulb
(0.372mol,1.5ep).Stirring is warmed up to 100 DEG C of interior temperature, and the accessory substance for producing is reclaimed in insulation reaction, condenser pipe air-distillation
Chloroform, after the clarification of question response liquid, insulation reaction 24 hours.Reaction is finished, and is cooled to 20 DEG C, and concentrated hydrochloric acid is added dropwise, and adjusts PH=3, complete
Finish, stir 30 minutes, be then cooled to 0 DEG C of interior temperature, insulated and stirred 2 hours, filtering, frozen water 50mL drip washing is drained, hot air circulation
80 DEG C of baking oven baking material 8 hours, obtains white solid 31g, 148~149 DEG C of fusing point.
The 5- chlor-2-thiophenecar-boxylic acids of embodiment 2
(1) 2- chlorothiophenes 30g (0.253mol), Heteroatom-aluminophosphate Zeolites molecular sieve 15g, trichloro-acetic chloride are put into flask
55.3g (0.305mol, 2ep), heats up 120 DEG C, insulation reaction 15 hours, vapor detection control terminal, and 2- chlorothiophenes content≤
2%, terminating reaction.Cooling down to room temperature, filtering is reclaimed catalyst and is applied mechanically, three excessive chloroethenes of filtrate decompression concentration and recovery
Acyl chlorides, remaining residual night is compound (2) crude product, and weight is 63g, and yield is more than 97%, crude product it is not purified can directly under
Single step reaction.
(2) compound (2) 65.5g (0.248mol), 15% potassium hydroxide solution 139g are put into reaction bulb
(0.375mol,1.5ep).Stirring is warmed up to 70 DEG C of interior temperature, and the accessory substance chlorine for producing is reclaimed in insulation reaction, condenser pipe air-distillation
It is imitative, after the clarification of question response liquid, insulation reaction 10 hours.Reaction is finished, and is cooled to 20 DEG C, and concentrated hydrochloric acid is added dropwise, and adjusts PH=1, is finished,
Stirring 30 minutes, is then cooled to 0 DEG C of interior temperature, and insulated and stirred 2 hours, filtering, frozen water 50mL drip washing is drained, and hot air circulation is dried
80 DEG C of case baking material 8 hours, obtains white solid 32g, 148~149 DEG C of fusing point.
The 5- chlor-2-thiophenecar-boxylic acids of embodiment 3
(1) 2- chlorothiophenes 30g (0.253mol), aluminium silicophosphate Zeolites Zeolites molecular sieve 6g (0.5W/ are put into flask
W), trichloro-acetic chloride 55.3g (0.305mol, 1.2ep), chloroform 150ml, heat up 60 DEG C, insulation reaction 72 hours, vapor detection
Control terminal, 2- chlorothiophene content≤2%, terminating reaction.Cooling down to room temperature, filtering is reclaimed catalyst and is applied mechanically, and filtrate subtracts
The excessive trichloro-acetic chloride of pressure concentration and recovery, remaining residual night is compound (2) crude product, and weight is 65.5g, yield be 98% with
On, crude product is not purified can directly next step reaction；
(2) compound (2) 65.5g (0.248mol), 50% sodium hydroxide solution 60g are put into reaction bulb
(0.744mol,3ep).Stirring is warmed up to 100 DEG C of interior temperature, and the accessory substance chlorine for producing is reclaimed in insulation reaction, condenser pipe air-distillation
It is imitative, after the clarification of question response liquid, insulation reaction 3 hours.Reaction is finished, and is cooled to 20 DEG C, and concentrated hydrochloric acid is added dropwise, and adjusts PH=2, is finished,
Stirring 30 minutes, is then cooled to 0 DEG C of interior temperature, and insulated and stirred 2 hours, filtering, frozen water 50mL drip washing is drained, and hot air circulation is dried
80 DEG C of case baking material 6 hours, obtains white solid 33g, 148~149 DEG C of fusing point.
The 5- chlor-2-thiophenecar-boxylic acids of embodiment 4
(1) 2- chlorothiophenes 30g (0.253mol), H- beta-zeolite molecular sieves 6g (0.5W/W), tribromo-acetyl are put into flask
Chlorine 55.3g (0.305mol, 1.2ep), 1,2- dichloroethanes 150ml, heat up 80 DEG C, insulation reaction 48 hours, vapor detection control
Terminal processed, 2- chlorothiophene content≤2%, terminating reaction.Cooling down to room temperature, filtering is reclaimed catalyst and is applied mechanically, filtrate decompression
The excessive trichloro-acetic chloride of concentration and recovery, remaining residual night is compound (2) crude product, and weight is 64g, and yield is more than 97%,
Crude product is not purified can directly next step reaction；
(2) compound (2) 65.5g (0.248mol), 15% sodium hydroxide solution 100g are put into reaction bulb
(0.375mol,1.5ep).Stirring is warmed up to 100 DEG C of interior temperature, and the accessory substance for producing is reclaimed in insulation reaction, condenser pipe air-distillation
Chloroform, after the clarification of question response liquid, insulation reaction 3 hours.Reaction is finished, and is cooled to 20 DEG C, and the concentrated sulfuric acid is added dropwise, and adjusts PH=3, complete
Finish, stir 30 minutes, be then cooled to 0 DEG C of interior temperature, insulated and stirred 2 hours, filtering, frozen water 50mL drip washing is drained, hot air circulation
80 DEG C of baking oven baking material 6 hours, obtains white solid 34g, 148~149 DEG C of fusing point.
The bromo- 2- thiophenic acids of the 5- of embodiment 5
(1) 2- bromothiophenes 32.6g (0.2mol), zeolite molecular sieve 6.5g, trichloro-acetic chloride 43.7g are put into flask
(0.24mol, 1.2ep), heats up 120 DEG C, insulation reaction 30 hours, vapor detection control terminal, and 2- bromothiophenes content≤
0.5%, terminating reaction.Cooling down to room temperature, filtering is reclaimed catalyst and is applied mechanically, and filtrate decompression reclaims excessive trichloro-acetic chloride
Remaining residual night is compound (III) crude product, and weight is 60.5g, and yield is more than 98%, and crude product is not purified can be directly next
Step.
(2) compound (III) 60.5g (0.196mol), 15% potassium hydroxide solution 146g are put into reaction bulb
(0.392mol,2ep).Stirring is warmed up to 80 DEG C of interior temperature, and the accessory substance bromine for producing is reclaimed in insulation reaction, condenser pipe air-distillation
It is imitative, after the clarification of question response liquid, insulation reaction 6 hours.Reaction is finished, and is cooled to 20 DEG C, and concentrated hydrochloric acid is added dropwise, and adjusts PH=3, is finished,
Stirring 30 minutes, is then cooled to 0 DEG C of interior temperature, and insulated and stirred 2 hours, filtering, frozen water 50ml drip washing is drained, and hot air circulation is dried
80 DEG C of case baking material 6 hours, obtains white solid 35g, 139~140 DEG C of fusing point.
The yield of above-mentioned each step is above 85%, and easy to operate, and implementation cost is cheap, and environmental protection is conducive to
Industrialized production is realized, with extremely strong industrial application value.
Claims (10)
1. a kind of 5- replaces the preparation method of -2- thiophenic acids, it is characterised in that methods described is carried out as follows：
(1) as raw material, zeolite molecular sieve is catalyst to the 2- halogenated thiophenes shown in formula 1, and trichloro-acetic chloride is acylating agent, in nothing
It is well mixed under the conditions of solvent or organic solvent, is reacted 15~72 hours at 60~130 DEG C, after reaction terminates, product
The post-treated compound (2) obtained shown in formula 2；The ratio between amount of material of 2- halogenated thiophenes and acylating agent shown in the formula 1
It is 1：1~2；
(2) alkaline solution will be added in the compound (2) shown in formula 2 and is stirred, at 70~100 DEG C, hydrolysis 3~24 is small
When, after reaction terminates, the post-treated target compound (3) obtained shown in formula 3 of product；Compound shown in the formula 3
(3) with alkaline solution in alkali material amount be 1:1.5~3.
Wherein, the X in formula 1, formula 3 is Cl, Br or I.
2. preparation method as claimed in claim 1, it is characterised in that in the step (1), the catalyst be HY zeolites,
HZSM-5 zeolites, H types silk zeolite, H- β zeolites, aluminium phosphate molecular sieve or aluminium silicophosphate molecular sieve.
3. preparation method as claimed in claim 1, it is characterised in that in step (1), the catalyst charge is with shown in formula 1
2- halogenated thiophene quality be calculated as 0.1~0.5g/g.
4. preparation method as claimed in claim 1, it is characterised in that in the step (1), organic solvent is chloroform or dichloro
Ethane.
5. preparation method as claimed in claim 1, it is characterised in that in the step (1), the addition of organic solvent is with formula 1
Shown 2- halogenated thiophenes are calculated as 0~5mL/g.
6. preparation method as claimed in claim 1, it is characterised in that in the step (1), the post processing of the product
Method is：After question response terminates, product is cooled to room temperature, through filtering, the recyclable catalyst of filter residue for obtaining, filtrate subtracts
The excessive trichloro-acetic chloride of pressure concentration and recovery, remaining residual night is compound (2) crude product shown in formula 2.
7. preparation method as claimed in claim 1, it is characterised in that in the step (2), the alkaline matter is hydroxide
Sodium or potassium hydroxide.
8. preparation method as claimed in claim 1, it is characterised in that in the step (2), described alkaline solution is alkali matter
Measure the aqueous solution of concentration 5~50%.
9. preparation method as claimed in claim 1, it is characterised in that in the step (2), the post-processing approach of product
For：After reaction terminates, product is cooled to 20~25 DEG C, acid adding regulation pH value is 1~3, and through cooling, filtering, frozen water drenches
Wash, drain, 70~80 DEG C of heated-air circulation oven baking material 6~8 hours obtains the target product shown in formula 3.
10. preparation method as claimed in claim 9, it is characterised in that pH value institute acid adding is adjusted described in the step (2) is
Hydrochloric acid or sulfuric acid.
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Cited By (2)
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| CN109280045A (en) * | 2018-12-18 | 2019-01-29 | 深圳市第二人民医院 | The synthetic method of the chloro- 2- thiophene chloride of Rivaroxaban intermediate 5- |
| CN115160290A (en) * | 2022-08-03 | 2022-10-11 | 广西大学 | Synthetic method of 2-thiopheneacetic acid |
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| CN115160290A (en) * | 2022-08-03 | 2022-10-11 | 广西大学 | Synthetic method of 2-thiopheneacetic acid |
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Application publication date: 20170613 |