CN109096245A - A kind of preparation method of 5- chlorothiophene -2- formic acid - Google Patents
A kind of preparation method of 5- chlorothiophene -2- formic acid Download PDFInfo
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- CN109096245A CN109096245A CN201811132076.4A CN201811132076A CN109096245A CN 109096245 A CN109096245 A CN 109096245A CN 201811132076 A CN201811132076 A CN 201811132076A CN 109096245 A CN109096245 A CN 109096245A
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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
Abstract
The present invention relates to intermediate technical fields, and 5- chlorothiophene -2- formic acid is disclosed, the raw material including following parts by weight proportion: 30-40 parts of 2- chlorothiophene, 10-20 parts of dimethylformamide, 1-2 parts of phosphorus oxychloride, 2-4 parts of 2-Thiophene Carboxylic Acid methyl esters, 1-3 parts of sodium nitrite, 5-10 parts of dust technology, 0.5-1 parts of methylene chloride, 3-5 parts of dilute hydrochloric acid.5- chlorothiophene -2- the formic acid, by the way that phosphorus oxychloride is added in organic matter, phosphorus oxychloride is a kind of industrial chemicals, for colorless and transparent fuming liquids, colorless and transparent stink with irritating and garlicky liquid, the violent smoke in humid air, it is reacted with water and is hydrolyzed into phosphoric acid and hydrogen chloride, organic matter reacts in the reaction vessel with phosphorus oxychloride, by 2-Thiophene Carboxylic Acid methyl esters, sodium nitrite and dust technology are successively into reaction vessel, sodium nitrite category strong oxidizer has reproducibility again, it can gradually aoxidize in air, surface then becomes sodium nitrate, to reach environmental protection, it is easy to operate, high income, purpose at low cost.
Description
Technical field
The present invention relates to intermediate technical field, specially a kind of preparation method of 5- chlorothiophene -2- formic acid.
Background technique
5- chlorothiophene -2- formic acid is an important intermediate in anticoagulation medicament, and anticoagulant can be used for treatment of vascular
The disease of interior embolism or thrombosis, pre- anti-stroke or other thrombotic diseases are certain solidifying in coagulation process by influencing
Blood factor prevents the drug of coagulation process, can be used for the disease of embolism or thrombosis in treatment of vascular, pre- anti-stroke or other
Thrombotic diseases are the drugs that coagulation process is prevented by the certain coagulation factors influenced in coagulation process, and normal person is due to having
Complete blood clotting system and anticoagulant and fibrinolytic system, so blood neither solidifies in the blood vessels nor bleeding, always freely
Its function is completed in flowing, but when body is in hypercoagulative state or anticoagulant and fibrinolytic weakens, then thrombotic disease occurs, often
Anticoagulant classification, heparin, heparin have very strong anticoagulation in vivo and in vitro, this is realized by antithrombin Ⅲ
, there is inhibiting effect to multiple links of coagulation process, effect is rapid, antiplatelet drug such as aspirin and persantine etc.
It is effective to thrombosis is prevented, because aspirin on platelet Cycloxygenase has inhibiting effect, and blood platelet epoxy can be prevented
Change enzyme and arachidonic acid is converted to prostaglandin intermediate, furthermore for example defibrase, Ahylysantinfarctase and Ahylysantinfarctase can for snake venom thrombolytics
Dissolving established thrombus makes revascularization, and Coumarins, there are commonly bicoumarin, neodicoumarin and acenocoumarols etc., by short of money
Antivitamin K make liver synthesis factor and the factor VII, Ⅸ and Ⅹ reduce and it is anticoagulant because medication start in vivo still have it is enough
Coagulation factor, therefore only competence exertion anticoagulation after these factor depletions, so its effect beginning is slower, but effect lasts
Time is longer, suitable for needing long period anticoagulant person such as Deep vain thrombosis and pulmonary embolism etc., causes bleeding when dosage is improper
When, in addition to vitamin K, most importantly defeated fresh blood is with supplement of coagulation factors.
So-called medicine intermediate, more actually for some industrial chemicals or chemical industry in drug synthesis process
Product, this chemical products do not need the production licence of drug, can produce in common chemical plant, as long as reaching
Rank, can be used to the synthesis of drug, China about needs raw material matched with chemical industry and more than 2000 kinds of intermediate, demand every year
Up to 2,500,000 tons or more, by development in more than 30 years, industrial chemicals needed for the production of China's medicine and intermediate can match substantially
Set, only small part need import, and since china natural resources are relatively abundanter, the prices of raw materials are lower, and it is real that there are many intermediates
Show a large amount of outlets, however the present 5- chlorothiophene -2- formic acid of synthesis mostly mainly passes through 2- chlorothiophene and manages reaction through normal-butyl, this
Kind mode not only needs largely to handle later period environmental protection, but also complicated for operation, and yield is lower, higher cost, so propose one kind
5- chlorothiophene -2- formic acid solves the above problems.
Summary of the invention
(1) the technical issues of solving
In view of the deficiencies of the prior art, the present invention provides a kind of 5- chlorothiophene -2- formic acid, have environmental protection, it is easy to operate,
High income, it is at low cost the advantages that, solve and not only need to a large amount of processing of later period environmental protection, but also is complicated for operation, yield is lower, at
This higher problem.
(2) technical solution
To realize above-mentioned environmental protection, easy to operate, high income, purpose at low cost, the invention provides the following technical scheme: a kind of
5- chlorothiophene -2- formic acid, the raw material including following parts by weight proportion: 30-40 parts of 2- chlorothiophene, dimethylformamide 10-20
Part, 1-2 parts of phosphorus oxychloride, 2-4 parts of 2-Thiophene Carboxylic Acid methyl esters, 1-3 parts of sodium nitrite, 5-10 parts of dust technology, methylene chloride 0.5-1
Part, 3-5 parts of dilute hydrochloric acid.
Preferably, 40 parts of 2- chlorothiophene, 20 parts of dimethylformamide, 2 parts of phosphorus oxychloride, 4 parts of 2-Thiophene Carboxylic Acid methyl esters, Asia
3 parts of sodium nitrate, 10 parts of dust technology, 1 part of methylene chloride, 5 parts of dilute hydrochloric acid.
Preferably, 30 parts of 2- chlorothiophene, 10 parts of dimethylformamide, 1 part of phosphorus oxychloride, 2 parts of 2-Thiophene Carboxylic Acid methyl esters, Asia
1 part of sodium nitrate, 5 parts of dust technology, 0.5 part of methylene chloride, 3 parts of dilute hydrochloric acid.
Preferably, 35 parts of 2- chlorothiophene, 15 parts of dimethylformamide, 1.5 parts of phosphorus oxychloride, 3 parts of 2-Thiophene Carboxylic Acid methyl esters,
2 parts of sodium nitrite, 8 parts of dust technology, 0.8 part of methylene chloride, 4 parts of dilute hydrochloric acid.
Another technical problem to be solved by the present invention is that a kind of preparation method of 5- chlorothiophene -2- formic acid is provided, including with
Lower step:
1) 2- chlorothiophene is weighed as 30-40 parts, dimethylformamide is weighed as 10-20 parts, while by 2- chlorothiophene
It is added sequentially in reaction vessel, the temperature of reaction vessel is controlled at 70-80 DEG C, and heat 1-2 with dimethylformamide
Hour, during heating, using reaction vessel to the internal stirring constantly carried out at the uniform velocity, make 2- chlorothiophene and dimethylformamide
It is adequately reacted in reaction vessel.
2) 10 DEG C after the reaction was completed, are cooled to using ice water, methylene chloride is weighed as 0.5-1 parts, in past reaction vessel
Middle addition methylene chloride carries out hybrid reaction using methylene chloride, generates organic matter, mention to the organic layer on organic matter surface
It takes.
3) phosphorus oxychloride is weighed 1-2 parts, phosphorus oxychloride then is added into the organic matter of extraction, by the organic matter of extraction
It is placed in reaction vessel, by the control of the temperature of reaction vessel at 50-60 DEG C, continuous heating and uniform stirring 2-4 hour, general
2-Thiophene Carboxylic Acid methyl esters is weighed as 2-4 parts, and sodium nitrite is weighed as 1-3 parts, and dust technology is weighed as 5-10 parts, by 2-Thiophene Carboxylic Acid
Methyl esters, sodium nitrite and dust technology are successively added into reaction vessel, are stirred to react 30-40 minutes.
4) dilute hydrochloric acid is weighed as 3-5 parts, and the PH of dilute hydrochloric acid is regulated and controled in 2-3, by the way that dilute hydrochloric acid is added to reaction
Solid filtering is carried out in container, by obtaining 5- chlorothiophene -2- formic acid after drying.
(3) beneficial effect
Compared with prior art, the present invention provides a kind of 5- chlorothiophene -2- formic acid, have it is following the utility model has the advantages that
1, the 5- chlorothiophene -2- formic acid, 2- chlorothiophene is a kind of toxic, inflammable nothing in preparation method through the invention
Color liquid, is commonly used for pharmaceutical intermediate, is added sequentially in reaction vessel by 2- chlorothiophene and dimethylformamide, dimethyl
Formamide is a kind of transparency liquid, and energy and water and most of organic solvent dissolve each other, it is the common solvent of chemical reaction, pure diformazan
Base formamide is that have off-odor, and technical grade or rotten dimethylformamide then have a fish like smell, because it contains dimethyl amine
Impurity, title source be the dimethyl substituent of formamide (amide of formic acid) due to it, and two methyl are all located at N
On (nitrogen) atom, dimethylformamide is high boiling polarity (hydrophily) non-protonic solvent, can promote SN2 reaction mechanism
It carries out, dimethylformamide is manufactured using methyl formate and dimethyl amine, and dimethylformamide is in highly basic such as sodium hydroxide
Or in the presence of strong acid such as hydrochloric acid or sulfuric acid be unstable (especially at high temperature), and be hydrolyzed to formic acid and dimethyl amine, 2-
Chlorothiophene and dimethylformamide are added in reaction vessel, the temperature of reaction vessel are controlled at 70-80 DEG C, and heat 1-
2 hours, after the reaction was completed, 10 DEG C are cooled to using ice water, easy to operate, cost is relatively low, and reaction vessel is added in methylene chloride
In, methylene chloride is colourless transparent liquid, there is the penetrating odor with similar ether, it is not soluble in water, it is dissolved in ethyl alcohol and ether, is
Non-combustible low boiling point solvent is commonly used to replace inflammable petroleum ether and ether, in methane molecule two hydrogen atoms replaced by chlorine and
The compound of generation, methylene chloride are colourless, transparent, heavier and volatile than water liquid, have the smell and sweet taste of similar ether, no
Burning, but the mixture of explosion is formed after mixing with high concentration oxygen, methylene chloride is slightly soluble in water, common organic with the overwhelming majority
Solvent dissolves each other, can also be miscible with arbitrary proportion with other chlorinated solvents, ether and ethyl alcohol, methylene chloride can be dissolved in quickly phenol,
In aldehyde, ketone, glacial acetic acid, triethyl phosphate, formamide, cyclohexylamine and ethyl acetoacetate, absolute dichloromethane contains equal bodies without flash-point
The solvent mixture of long-pending methylene chloride and gasoline, solvent naphtha or toluene be it is nonflammable, mixed using methylene chloride
Reaction is closed, organic matter is generated, the organic layer on organic matter surface is extracted.
2, the 5- chlorothiophene -2- formic acid, by the way that phosphorus oxychloride is added in organic matter, phosphorus oxychloride is that a kind of industrial chemical is former
Material is colorless and transparent fuming liquids, colorless and transparent stink with irritating and garlicky liquid, acutely sends out in humid air
Cigarette reacts with water and is hydrolyzed into phosphoric acid and hydrogen chloride, and organic matter reacts in the reaction vessel with phosphorus oxychloride, by 2-Thiophene Carboxylic Acid first
Successively into reaction vessel, sodium nitrite category strong oxidizer has reproducibility again for ester, sodium nitrite and dust technology, in air can be by
It gradually aoxidizes, surface then becomes sodium nitrate, can also be oxidized agent and be aoxidized, and meets weak acid and decomposes to give off brown nitrogen dioxide gas, meets
Strong oxidizer can be also oxidized, especially ammonium salt, such as at normal temperature with ammonium nitrate, ammonium persulfate, can interact generation
High fever, if being converted into nitrite, standard is the kg body weight of 0~4.2 ㎎/60, is used and is eaten by this standard, not to human body
It will cause harm, sodium nitrite is toxic, there's a rumor that sodium nitrite is carcinogen, but in fact sodium nitrite is not carcinogenic
Substance, carcinogenic is the nitrosamine that sodium nitrite generates under certain condition, and dilute hydrochloric acid, i.e. mass fraction are lower than 20% salt
The chemical formula of acid, solute is HCl, and dilute hydrochloric acid is a kind of colorless clear liquid, is in highly acid, and irritant smell belongs to medicinal
Auxiliary material, pH adjusting agent should be placed in vial and be sealed, and be mainly used for laboratory carbon dioxide and hydrogen, scale removal,
Medicinal aspect mainly can treat gastric acid deficiency, and dilute hydrochloric acid is added to progress solid filtering in reaction vessel, after drying
5- chlorothiophene -2- formic acid is obtained, thus reached environmental protection, easy to operate, high income, purpose at low cost.
Specific embodiment
Below in conjunction with the embodiment of the present invention, technical solution in the embodiment of the present invention is clearly and completely retouched
It states, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the present invention
In embodiment, every other implementation obtained by those of ordinary skill in the art without making creative efforts
Example, shall fall within the protection scope of the present invention.
Embodiment one:
A kind of 5- chlorothiophene -2- formic acid, the raw material including following parts by weight proportion: 40 parts of 2- chlorothiophene, dimethyl methyl
It is 20 parts of amide, 2 parts of phosphorus oxychloride, 4 parts of 2-Thiophene Carboxylic Acid methyl esters, 3 parts of sodium nitrite, 10 parts of dust technology, 1 part of methylene chloride, dilute
5 parts of hydrochloric acid.
A kind of preparation method of 5- chlorothiophene -2- formic acid, which comprises the following steps:
1) 2- chlorothiophene is weighed as 40 parts, dimethylformamide is weighed as 20 parts, while by 2- chlorothiophene and diformazan
Base formamide is added sequentially in reaction vessel, and the temperature of reaction vessel is controlled at 70-80 DEG C, and is heated 1-2 hours,
During heating, using reaction vessel to the internal stirring constantly carried out at the uniform velocity, reacting 2- chlorothiophene and dimethylformamide
Container adequately reacts.
2) 10 DEG C after the reaction was completed, are cooled to using ice water, methylene chloride is weighed as 1 part, is being added into reaction vessel
Enter methylene chloride, carries out hybrid reaction using methylene chloride, generate organic matter, the organic layer on organic matter surface is extracted.
3) phosphorus oxychloride is weighed 2 parts, phosphorus oxychloride then is added into the organic matter of extraction, the organic matter of extraction is put
It is placed in reaction vessel, by the control of the temperature of reaction vessel at 50-60 DEG C, continuous heating and uniform stirring 2-4 hours, by 2-
Thiophene carboxylic acid methyl ester is weighed as 4 parts, and sodium nitrite is weighed as 3 parts, and dust technology is weighed as 10 parts, by 2-Thiophene Carboxylic Acid methyl esters, Asia
Sodium nitrate and dust technology are successively added into reaction vessel, are stirred to react 30-40 minutes.
4) dilute hydrochloric acid is weighed as 5 parts, and the PH of dilute hydrochloric acid regulation is held in 2-3 by the way that dilute hydrochloric acid is added to reaction
Solid filtering is carried out in device, by obtaining 5- chlorothiophene -2- formic acid after drying.
Embodiment two:
A kind of 5- chlorothiophene -2- formic acid, the raw material including following parts by weight proportion: 30 parts of 2- chlorothiophene, dimethyl methyl
It is 10 parts of amide, 1 part of phosphorus oxychloride, 2 parts of 2-Thiophene Carboxylic Acid methyl esters, 1 part of sodium nitrite, 5 parts of dust technology, 0.5 part of methylene chloride, dilute
3 parts of hydrochloric acid.
A kind of preparation method of 5- chlorothiophene -2- formic acid, which comprises the following steps:
1) 2- chlorothiophene is weighed as 30 parts, dimethylformamide is weighed as 10 parts, while by 2- chlorothiophene and diformazan
Base formamide is added sequentially in reaction vessel, and the temperature of reaction vessel is controlled at 70-80 DEG C, and is heated 1-2 hours,
During heating, using reaction vessel to the internal stirring constantly carried out at the uniform velocity, reacting 2- chlorothiophene and dimethylformamide
Container adequately reacts.
2) 10 DEG C after the reaction was completed, are cooled to using ice water, methylene chloride is weighed as 0.5 part, into reaction vessel
Methylene chloride is added, carries out hybrid reaction using methylene chloride, generates organic matter, the organic layer on organic matter surface is mentioned
It takes.
3) phosphorus oxychloride is weighed 1 part, phosphorus oxychloride then is added into the organic matter of extraction, the organic matter of extraction is put
It is placed in reaction vessel, by the control of the temperature of reaction vessel at 50-60 DEG C, continuous heating and uniform stirring 2-4 hours, by 2-
Thiophene carboxylic acid methyl ester is weighed as 2 parts, and sodium nitrite is weighed as 1 part, and dust technology is weighed as 5 parts, by 2-Thiophene Carboxylic Acid methyl esters, nitrous
Sour sodium and dust technology are successively added into reaction vessel, are stirred to react 30-40 minutes.
4) dilute hydrochloric acid is weighed as 3 parts, and the PH of dilute hydrochloric acid regulation is held in 2-3 by the way that dilute hydrochloric acid is added to reaction
Solid filtering is carried out in device, by obtaining 5- chlorothiophene -2- formic acid after drying.
Embodiment three:
A kind of 5- chlorothiophene -2- formic acid, the raw material including following parts by weight proportion: 35 parts of 2- chlorothiophene, dimethyl methyl
15 parts of amide, 1.5 parts of phosphorus oxychloride, 3 parts of 2-Thiophene Carboxylic Acid methyl esters, 2 parts of sodium nitrite, 8 parts of dust technology, 0.8 part of methylene chloride,
4 parts of dilute hydrochloric acid.
A kind of preparation method of 5- chlorothiophene -2- formic acid, which comprises the following steps:
1) 2- chlorothiophene is weighed as 35 parts, dimethylformamide is weighed as 15 parts, while by 2- chlorothiophene and diformazan
Base formamide is added sequentially in reaction vessel, and the temperature of reaction vessel is controlled at 70-80 DEG C, and is heated 1-2 hours,
During heating, using reaction vessel to the internal stirring constantly carried out at the uniform velocity, reacting 2- chlorothiophene and dimethylformamide
Container adequately reacts.
2) 10 DEG C after the reaction was completed, are cooled to using ice water, methylene chloride is weighed as 0.8 part, into reaction vessel
Methylene chloride is added, carries out hybrid reaction using methylene chloride, generates organic matter, the organic layer on organic matter surface is mentioned
It takes.
3) phosphorus oxychloride is weighed 1.5 parts, phosphorus oxychloride then is added into the organic matter of extraction, by the organic matter of extraction
It is placed in reaction vessel, by the control of the temperature of reaction vessel at 50-60 DEG C, continuous heating and uniform stirring 2-4 hour, general
2-Thiophene Carboxylic Acid methyl esters is weighed as 3 parts, and sodium nitrite is weighed as 2 parts, and dust technology is weighed as 8 parts, by 2-Thiophene Carboxylic Acid methyl esters, Asia
Sodium nitrate and dust technology are successively added into reaction vessel, are stirred to react 30-40 minutes.
4) dilute hydrochloric acid is weighed as 4 parts, and the PH of dilute hydrochloric acid regulation is held in 2-3 by the way that dilute hydrochloric acid is added to reaction
Solid filtering is carried out in device, by obtaining 5- chlorothiophene -2- formic acid after drying.
The beneficial effects of the present invention are: 2- chlorothiophene is a kind of toxic, inflammable nothing in preparation method through the invention
Color liquid, is commonly used for pharmaceutical intermediate, is added sequentially in reaction vessel by 2- chlorothiophene and dimethylformamide, dimethyl
Formamide is a kind of transparency liquid, and energy and water and most of organic solvent dissolve each other, it is the common solvent of chemical reaction, pure diformazan
Base formamide is that have off-odor, and technical grade or rotten dimethylformamide then have a fish like smell, because it contains dimethyl amine
Impurity, title source be the dimethyl substituent of formamide (amide of formic acid) due to it, and two methyl are all located at N
On (nitrogen) atom, dimethylformamide is high boiling polarity (hydrophily) non-protonic solvent, can promote SN2 reaction mechanism
It carries out, dimethylformamide is manufactured using methyl formate and dimethyl amine, and dimethylformamide is in highly basic such as sodium hydroxide
Or in the presence of strong acid such as hydrochloric acid or sulfuric acid be unstable (especially at high temperature), and be hydrolyzed to formic acid and dimethyl amine, 2-
Chlorothiophene and dimethylformamide are added in reaction vessel, the temperature of reaction vessel are controlled at 70-80 DEG C, and heat 1-
2 hours, after the reaction was completed, 10 DEG C are cooled to using ice water, easy to operate, cost is relatively low, and reaction vessel is added in methylene chloride
In, methylene chloride is colourless transparent liquid, there is the penetrating odor with similar ether, it is not soluble in water, it is dissolved in ethyl alcohol and ether, is
Non-combustible low boiling point solvent is commonly used to replace inflammable petroleum ether and ether, in methane molecule two hydrogen atoms replaced by chlorine and
The compound of generation, methylene chloride are colourless, transparent, heavier and volatile than water liquid, have the smell and sweet taste of similar ether, no
Burning, but the mixture of explosion is formed after mixing with high concentration oxygen, methylene chloride is slightly soluble in water, common organic with the overwhelming majority
Solvent dissolves each other, can also be miscible with arbitrary proportion with other chlorinated solvents, ether and ethyl alcohol, methylene chloride can be dissolved in quickly phenol,
In aldehyde, ketone, glacial acetic acid, triethyl phosphate, formamide, cyclohexylamine and ethyl acetoacetate, absolute dichloromethane contains equal bodies without flash-point
The solvent mixture of long-pending methylene chloride and gasoline, solvent naphtha or toluene be it is nonflammable, mixed using methylene chloride
Reaction is closed, organic matter is generated, the organic layer on organic matter surface is extracted, by the way that phosphorus oxychloride, trichlorine are added in organic matter
Oxygen phosphorus is a kind of industrial chemicals, is colorless and transparent fuming liquids, colorless and transparent stink with irritating and garlicky liquid
Body, the violent smoke in humid air, reacts with water and is hydrolyzed into phosphoric acid and hydrogen chloride, and organic matter and phosphorus oxychloride are in reaction vessel
Middle reaction, by 2-Thiophene Carboxylic Acid methyl esters, sodium nitrite and dust technology successively into reaction vessel, sodium nitrite category strong oxidizer is again
There is reproducibility, can gradually aoxidize in air, surface then becomes sodium nitrate, can also be oxidized agent and be aoxidized, and meets weak acid decomposition and puts
Brown nitrogen dioxide gas out, meeting strong oxidizer can also be oxidized, especially ammonium salt, such as with ammonium nitrate and ammonium persulfate normal
Under temperature, it can interact and generate high fever, if being converted into nitrite, standard is the kg body weight of 0~4.2 ㎎/60, by this mark
Standard is used and is eaten, and will not be caused damages to human body, and sodium nitrite is toxic, there's a rumor that sodium nitrite is carcinogen, but thing
Sodium nitrite is not carcinogen in reality, and carcinogenic is the nitrosamine that sodium nitrite generates under certain condition, dilute hydrochloric acid, i.e.,
Mass fraction is lower than 20% hydrochloric acid, and the chemical formula of solute is HCl, and dilute hydrochloric acid is a kind of colorless clear liquid, is in highly acid, has
Penetrating odor belongs to pharmaceutic adjuvant, and pH adjusting agent should be placed in vial and be sealed, and is mainly used for laboratory system two
Carbonoxide and hydrogen, scale removal, medicinal aspect mainly can treat gastric acid deficiency, and dilute hydrochloric acid is added in reaction vessel and carries out
Solid filtering, by obtaining 5- chlorothiophene -2- formic acid after drying, to reach environmental protection, easy to operate, high income is at low cost
Purpose.
It although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, can be with
A variety of variations, modification, replacement can be carried out to these embodiments without departing from the principles and spirit of the present invention by understanding
And modification, the scope of the present invention is defined by the appended.
Claims (5)
1. a kind of 5- chlorothiophene -2- formic acid, which is characterized in that the raw material including following parts by weight proportion: 2- chlorothiophene 30-40
Part, 10-20 parts of dimethylformamide, 1-2 parts of phosphorus oxychloride, 2-4 parts of 2-Thiophene Carboxylic Acid methyl esters, 1-3 parts of sodium nitrite, dust technology
5-10 parts, 0.5-1 parts of methylene chloride, 3-5 parts of dilute hydrochloric acid.
2. a kind of 5- chlorothiophene -2- formic acid according to claim 1, which is characterized in that matched including following parts by weight
Raw material: 40 parts of 2- chlorothiophene, 20 parts of dimethylformamide, 2 parts of phosphorus oxychloride, 4 parts of 2-Thiophene Carboxylic Acid methyl esters, sodium nitrite 3
Part, 10 parts of dust technology, 1 part of methylene chloride, 5 parts of dilute hydrochloric acid.
3. a kind of 5- chlorothiophene -2- formic acid according to claim 1, which is characterized in that matched including following parts by weight
Raw material: 30 parts of 2- chlorothiophene, 10 parts of dimethylformamide, 1 part of phosphorus oxychloride, 2 parts of 2-Thiophene Carboxylic Acid methyl esters, sodium nitrite 1
Part, 5 parts of dust technology, 0.5 part of methylene chloride, 3 parts of dilute hydrochloric acid.
4. a kind of 5- chlorothiophene -2- formic acid according to claim 1, which is characterized in that matched including following parts by weight
Raw material: 35 parts of 2- chlorothiophene, 15 parts of dimethylformamide, 1.5 parts of phosphorus oxychloride, 3 parts of 2-Thiophene Carboxylic Acid methyl esters, sodium nitrite
2 parts, 8 parts of dust technology, 0.8 part of methylene chloride, 4 parts of dilute hydrochloric acid.
5. a kind of preparation method of 5- chlorothiophene -2- formic acid, which comprises the following steps:
1) 2- chlorothiophene is weighed as 30-40 parts, dimethylformamide is weighed as 10-20 parts, while by 2- chlorothiophene and two
Methylformamide is added sequentially in reaction vessel, and the temperature of reaction vessel is controlled at 70-80 DEG C, and is heated 1-2 hours,
During heating, make 2- chlorothiophene and dimethylformamide anti-the internal stirring constantly carried out at the uniform velocity using reaction vessel
Container is answered adequately to react；
2) 10 DEG C after the reaction was completed, are cooled to using ice water, methylene chloride is weighed as 0.5-1 parts, is being added into reaction vessel
Enter methylene chloride, carries out hybrid reaction using methylene chloride, generate organic matter, the organic layer on organic matter surface is extracted；
3) phosphorus oxychloride is weighed 1-2 parts, phosphorus oxychloride then is added into the organic matter of extraction, the organic matter of extraction is placed
In reaction vessel, by the control of the temperature of reaction vessel at 50-60 DEG C, continuous heating and uniform stirring 2-4 hours, by 2- thiophene
Pheno carboxylate methyl ester is weighed as 2-4 parts, and sodium nitrite is weighed as 1-3 parts, and dust technology is weighed as 5-10 parts, by 2-Thiophene Carboxylic Acid first
Ester, sodium nitrite and dust technology are successively added into reaction vessel, are stirred to react 30-40 minutes；
4) dilute hydrochloric acid is weighed as 3-5 parts, and the PH of dilute hydrochloric acid is regulated and controled in 2-3, by the way that dilute hydrochloric acid is added to reaction vessel
Middle progress solid filtering, by obtaining 5- chlorothiophene -2- formic acid after drying.
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| CN106518840A (en) * | 2016-11-17 | 2017-03-22 | 山东铂源药业有限公司 | Synthetic method of 5-chloro-2-thiophenecarboxylic acid |
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2018
- 2018-09-27 CN CN201811132076.4A patent/CN109096245A/en active Pending
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| WO1994012505A1 (en) * | 1992-11-23 | 1994-06-09 | Pfizer Inc. | Regioselective synthesis of 4-chloro-2-thiophenecarboxylic acid |
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| CN102993165A (en) * | 2012-12-05 | 2013-03-27 | 青岛前线生物工程有限公司 | Synthesis method of 5-chlorothiophene-2-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 |
| CN106518840A (en) * | 2016-11-17 | 2017-03-22 | 山东铂源药业有限公司 | Synthetic method of 5-chloro-2-thiophenecarboxylic acid |
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