CN106146455A - 3-alkoxy thiophene derivant and preparation method thereof - Google Patents
3-alkoxy thiophene derivant and preparation method thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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 invention provides a kind of new 3-alkoxy thiophene derivant and preparation method thereof.The structure of described 3-alkoxy thiophene derivant is as described in chemical formula 1, its preparation method comprises the following steps: after the compound of the compound of following chemical formula 2 Yu following chemical formula 3 is carried out reaction acquisition product by (A), the hydrolysis of described product prepares the compound of following chemical formula 4；(B) compound of prepared chemical formula 4 is carried out monoalkylation in a solvent, prepare the compound of following chemical formula 5；And the compound of prepared chemical formula 5 is heated to 80 DEG C～300 DEG C and carries out decarboxylic reaction by (C) under solvent free conditions；In chemical formula, R1And R2Being each independently alkyl, X is halogen.The preparation method of the present invention has can the place of production efficient, the high advantage of preparing 3-alkoxy thiophene derivant.
Description
Technical field
The present invention relates to the new preparation process of 3-alkoxy thiophene derivant, being specifically related to one can be effective
The method that ground high yield prepares 3-alkoxy thiophene derivant, and the 3-alkoxyl prepared by the method
Thiophene derivant.
Background technology
The 3-alkoxy thiophene of following Formula I is intermediate important in prostaglandin synthesis, is considered
It it is the intermediate that synthesis difficulty is big.And, 3-alkoxy thiophene has consequence in pharmacy.
[Formula I]
To this, there is the research (Synthetic of a lot of preparation method for 3-alkoxy thiophene derivant so far
Metals 2014,188,156-160；New J.Chem.2010,34,2558-2563 etc.).But, described
There is the problem that yield is low, impurity is many or cost is high in published synthetic method.
Prior art document
Non-patent document:
(non-patent document 1) Synthetic Metals 2014,188,156-160
(non-patent document 2) New J.Chem.2010,34,2558-2563
(non-patent document 3) J.Med.Chem., 1997,40 (25), 4053-4068
(non-patent document 4) J.Het.Chem.2003,40 (1) 1-23
(non-patent document 5) Bioorg.Med.Chem.Lett.2001,11 (11), 1407-1410
(non-patent document 6) J.Med.Chem., 2003,46 (23), 4910-4925
Summary of the invention
Solve the technical problem that:
Present invention solves the technical problem that being to provide one can effectively prepare 3-alkoxy thiophene derivant
Method.
Meanwhile, the present invention other problem solved is that provides a kind of preparation method by the present invention to obtain
3-alkoxy thiophene derivant.
The technical issues that need to address of the present invention are not limited only to the problems referred to above, also include those skilled in the art
Other the NM problems that can be expressly understood that.
Issue-resolution:
The invention provides the preparation method of the 3-alkoxy thiophene derivant of a kind of following chemical formula 1, should
Method comprises the following steps: (A) is by the compound of the compound of following chemical formula 2 Yu following chemical formula 3
After carrying out reaction acquisition product, the hydrolysis of described product is prepared the compound of following chemical formula 4；
(B) compound of prepared chemical formula 4 is carried out monoalkylation in a solvent
(monoalkylation) compound of following chemical formula 5, is prepared；And (C) is by prepared chemical formula 5
Compound be heated to 80 DEG C～300 DEG C under solvent free conditions and carry out decarboxylic reaction
(decarboxylation)。
[chemical formula 1]
[chemical formula 2]
[chemical formula 3]
[chemical formula 4]
[chemical formula 5]
In chemical formula, R1And R2Being each independently alkyl, X is halogen.Preferably, described R1
And R2It is each independently C1-C4Alkyl；More preferably methyl (methyl).It is also preferable that institute
Stating X is bromine.
Product in described step (A) can be the compound of chemical formula 2-1.
[chemical formula 2-1]
In chemical formula, R1And R2It is each independently alkyl.Preferably, described R1And R2Each
Independently be C1-C4Alkyl；It is highly preferred that described R1And R2For methyl (methyl).
Described step (A) is characterised by comprising the following steps: (A-1) is by the compound of described chemical formula 2
In solvent and alkali, the compound with described chemical formula 3 carries out reaction acquisition product；And (A-2)
The product obtained in step (A-1) is hydrolyzed in the alkali of aqueous liquid, prepares chemical formula 4
Compound.
Described step (A-1) is characterised by comprising the following steps: (A-1a) at 15 DEG C～30 DEG C, by molten
Agent contacts with the compound of described chemical formula 2, to obtain the contact procedure of product of contact；(A-1b)
At 15 DEG C～30 DEG C, alkali is added in the product of contact obtained to step (A-1a), to obtain interpolation
The first time of product adds step；(A-1c) at 35 DEG C～45 DEG C, the interpolation that will obtain in step (A-1b)
Product is stirred, to obtain the first time whipping step of the first stirring product；(A-1d) described first
Stirring product adds the compound of described chemical formula 3, to obtain the second time interpolation step of affixture；
(A-1e) at 80 DEG C～100 DEG C, the affixture that the second time of step (A-1d) is added step acquisition enters
Row stirring, to obtain the second time whipping step of the second stirring product；And (A-1f) is by step (A-1e)
In the second stirring product non-polar solven carry out extraction and obtain after extraction product, described extraction product is entered
Row concentrates, to obtain the purification step of enriched product.
Solvent in described step (A-1) be selected from dimethylformamide, dichloromethane, benzene, toluene, four
One or more non-polar solvens in chloromethane, ether, diisopropyl ether and dimethyl sulfoxide
(nonpolar solvent)。
Alkali in described step (A-1) is selected from K2CO3、Na2CO3, in KOH and NaOH one
Plant or multiple.
Non-polar solven in described step (A-1f) be selected from dimethylformamide, dichloromethane, benzene,
One or more in toluene, four chloromethanes, ether, diisopropyl ether and dimethyl sulfoxide.
Described step (A-2) can comprise the following steps that (A-2a) at 15 DEG C～30 DEG C, in step (A-1)
Product is added the alkali (base) of aqueous liquid, to obtain the interpolation step of affixture；(A-2b)
At 70 DEG C～90 DEG C, the affixture that step (A-2a) obtains is stirred, to obtain stirring product
Whipping step；And (A-2c) adds the step of acid in the stirring product of step (A-2b).
Alkali in described step (A-2) can be K2CO3、Na2CO3, in KOH and NaOH one
Plant or multiple.
Described step (A-2c) can be to be adjusted to-10 DEG C～0 DEG C by a temperature of the stirring product of step (A-2b)
The described acid of rear interpolation to pH value is 1.
Acid in described step (A-2c) can be hydrochloric acid, nitric acid, sulphuric acid or acetic acid.
Described step (B) can comprise the following steps that (Ba) at 0 DEG C～10 DEG C, by solvent and chemical formula 4
Compound contact, to obtain the contact procedure of product of contact；(Bb) at 0 DEG C～10 DEG C, in step
The product of contact of (Ba) drips sulphuric acid suddenly, to obtain the dropping step of dropping product；(Bc) exist
At 10 DEG C～30 DEG C, the dropping product of step (Bb) is stirred 2 hours～6 hours, to obtain stirring product
Whipping step；And described stirring product is carried out the purification step that refines by (Bd).
Solvent in described step (Ba) can be the one in methanol, isopropanol and butanol or many
Plant polar solvent.
Refining in described step (Bd) can include filtration step, extraction step, concentration step and do
Dry step.
Described refining can use selected from dimethylformamide, dichloromethane, benzene, toluene, four chlorination first
One or more non-polar solvens in alkane, ether, diisopropyl ether and dimethyl sulfoxide.
Described step (C) can be carried out at 160 DEG C～240 DEG C.
Described step (C) can carry out 6 hours～48 hours.
The compound of described chemical formula 2 can be commercially available prod or the product prepared.
If the compound of described chemical formula 2 is the product prepared, described preparation method is the most permissible
Comprise the following steps: solvent, at-10 DEG C～5 DEG C, is contacted by (a) with metallic sodium, to obtain contact
The contact procedure of product；B the compound of following chemical formula 6, at-10 DEG C～10 DEG C, is dropped to step by ()
In the product of contact of (a), to obtain the first time dropping step of the first dropping product；C () is at-10 DEG C～10 DEG C
Under, the compound of following chemical formula 7 is dropped in the first dropping product obtained in step (b), to obtain
Obtain the second time dropping step of the second dropping product；(d) at 15 DEG C～30 DEG C, by what step (c) obtained
Second dropping product is stirred, to obtain the final whipping step stirring product；E () finally stirs toward described
Mix and product adds acid, to obtain the step of affixture；And the interpolation obtained in step (e) is produced by (f)
Thing carries out the purification step extracting and concentrating, thus prepares the compound of described chemical formula 2.
[chemical formula 6]
[chemical formula 7]
In chemical formula, R2For alkyl.Preferably, described R2For C1-C4Alkyl；Further preferably
Can be methyl (methyl).
It is 2 that described step (e) can use acid to carry out being acidified to pH value.
Extraction in described step (f) can use selected from dimethylformamide, dichloromethane, benzene, toluene,
One or more non-polar solvens in four chloromethanes, ether, diisopropyl ether and dimethyl sulfoxide.
Meanwhile, the invention provides the 3-of the chemical formula 1 that a kind of preparation method by the present invention obtains
Alkoxy thiophene derivant.
The beneficial effect of the invention:
By the present invention, 3-alkoxy thiophene derivant can be prepared in the place of production efficient, high.
Accompanying drawing explanation
Fig. 1 is the flow chart of an embodiment of the invention.
Detailed description of the invention
In following embodiment, by with reference to embodiment described below, it is possible to be expressly understood this
Bright advantage and feature also have its Method Of Accomplishment.But the present invention is not to be limited as enforcement discussed below
These embodiments can be carried out any accommodation and improvement by mode, and following embodiment is only used as explaining also
Implement the present invention to be used so that it is provide and know the protection model of the present invention to those of ordinary skill in the art
Enclosing, protection scope of the present invention is determined by appended claim and equivalent thereof.
In the specification, identical element represents with identical reference.It addition, " with/
Or " include mentioned corresponding element respectively with all scenario simultaneously.
The term used in this specification is used for embodiment is described, is not meant to carry out the present invention appointing
What limits.In addition to special instruction, the singulative in this specification also includes plural form.Saying
Structure mentioned by representing " the including (comprises) " and/or " including (comprising) " used in bright book
Key element, step, action and/or component is become to be not precluded from least one other elements, step, action
And/or the existence of component or additional.
A kind of method that the invention provides compound preparing chemical formula 1.
[chemical formula 1]
In chemical formula 1, R1For alkyl；Can be preferably C1To C4Alkyl；Further preferably
Ground is methyl.The compound of described chemical formula 1 is 3-alkoxy thiophene derivant, is prostaglandin synthesis
In important intermediate it is considered to be the synthesis big intermediate of difficulty, play an important role in pharmacy
(with reference to J.Med.Chem., 1997,40 (25), pp 4053-4068；J.Het.Chem.2003,40(1)
1-23；Bioorg.Med.Chem.Lett.2001,11(11),1407-1410；J.Med.Chem.,2003,
46 (23), pp 4910-4925. etc.).And then, 3-alkoxy thiophene derivant in described chemical formula 1,
R1For alkyl；Can be preferably C1To C4Alkyl；It is further preferably methyl, before can be used for
The synthesis of row parathyrine, for pharmaceutical field.
Hereinafter, by the following drawings and reaction equation, the 3-alkoxyl of the present invention is further described
The new preparation method of thiophene derivant.
Such as Fig. 1, an embodiment of the invention comprises the following steps: the compound of (A) chemical formula 4
Preparation, the preparation of the compound of (B) chemical formula 5, and (C) decarboxylic reaction.
Described step (A) is for carry out the compound of following chemical formula 2 with the compound of following chemical formula 3
After reaction obtains product, the hydrolysis of described product is prepared the compound of following chemical formula 4.
[chemical formula 2]
[chemical formula 3]
[chemical formula 4]
In chemical formula, R1And R2It is each independently alkyl；Preferably, described R1And R2Permissible
For C1-C4Alkyl；More preferably methyl.Meanwhile, the X in chemical formula is halogen；It is preferably bromine.
The compound entitled 3-hydroxy thiophene-2-alkyl carboxylates (alkyl of the compound of chemical formula 2
3-hydroxythiophene-2-carboxylate)。
Meanwhile, described step (B) is for carry out monoalkyl in a solvent by the compound of prepared chemical formula 4
Change reaction (monoalkylation), prepare compound in following chemical formula 5.
[chemical formula 5]
In chemical formula, R1For alkyl；It is preferably C1-C4Alkyl；More preferably methyl.
Meanwhile, described step (C) is by the compound of prepared chemical formula 5 under solvent free conditions
It is heated to 80 DEG C～300 DEG C and carries out decarboxylic reaction (decarboxylation).
The compound of chemical formula 2 is the parent material of this preparation method, can be by following reaction equation 1
Generate or commercially available prod.This mode is one embodiment of the present invention, is not limited to this, also can lead to
Cross other preparation methoies well known in the art and obtain the compound of chemical formula 2 in the present invention, or purchased from commercially available
Product.
[reaction equation 1]
Specifically, the 3-hydroxy thiophene-2-alkyl carboxylates of chemical formula 2 can be prepared by following steps: (a)
Contact procedure, (b) dropping step for the first time, (c) second time dropping step, (d) whipping step, (e) adds
Step, and (f) purification step.
Contact procedure (a) can be solvent to carry out with metallic sodium at-10 DEG C～5 DEG C contact acquisition contact produce
Thing.Solvent can be but be not limited to polar solvent, such as, and methanol, isopropanol and/or butanol.Excellent
Selection of land, carries out contact procedure at-4 DEG C～4 DEG C.
Dropping step (b) can be to be dissolved in and solvent in contact procedure by the compound of chemical formula 6 for the first time
In identical solvent, at-10 DEG C～10 DEG C, dropped to the product of contact in step (a) obtains first
Dropping product.Preferably, carry out dripping step for the first time at-4 DEG C～4 DEG C.
Second time dropping step (c) can be to be dissolved in and solvent in contact procedure by the compound of chemical formula 7
In identical solvent, at-10 DEG C～10 DEG C, dropped to the dropping product in step (b) obtains second
Dropping product.Preferably, at-4 DEG C～4 DEG C, carry out second time and drip step.
Whipping step (d) can be, after second time drips step, to drip second at 15 DEG C～30 DEG C
Product is stirred obtaining and finally stirs product.At this moment, the compound of chemical formula 2 is generated.Final stirring
Product is in the state not including parent material.Stirring in whipping step (d) can be carried out 1.5 hours～4
Hour, it is preferable that 1.5 hours～2 hours can be carried out.Preferably, it is stirred at 18 DEG C～26 DEG C.
Adding step (e) can be to add acid in described final stirring product to obtain affixture, for acidifying
Step.In one embodiment, after described interpolation step can concentrate finally stirring product,
Being acidified to pH value with acid is 2.Acid in the present invention can be regulation material used by pH value, but not
It is limited to such as, hydrochloric acid, nitric acid, sulphuric acid and/or acetic acid etc..
After adding step, by purification step, the compound of described chemical formula 2 is refined.Refined
Step can be the step carrying out affixture extracting and concentrating, specifically, it may include by affixture
Carry out extraction with solvent and obtain the extraction step of extraction product；And the extraction product in extraction step is entered
Row concentrates the concentration step obtaining enriched product.Can be prepared by described purification step after purifying further
The compound of chemical formula 2.
In one embodiment, described extraction step can be with solvent, affixture to be carried out extraction to obtain
Obtain the step of extraction product.Specifically, available solvent carries out extraction and obtains solvent layer affixture, will
Solvent layer water carries out the methods such as washing.Solvent can be but be not limited to non-polar solven, such as, and two
Methylformamide, dichloromethane, benzene, toluene, four chloromethanes, ether, diisopropyl ether and/or dimethyl
Sulfoxide etc..Meanwhile, described concentration step can be to use anhydrous MgSO4Deng will extraction product contain
Water is removed, and is removed by solvent with rotary concentrator etc., is concentrated the step obtaining enriched product.
Can disposably prepare the compound of the chemical formula 2 of 200～500g by the way.
Using the compound of chemical formula 2 as parent material, can be by the synthesis path system of following reaction equation 2
Obtain the compound of chemical formula 1.
[reaction equation 2]
Hereinafter, will be explained in synthesis condition and the order of each step.
Step (A)
After the compound of the compound of chemical formula 2 Yu chemical formula 3 is carried out reaction acquisition product, will
Product hydrolysis prepares the compound of chemical formula 4.
Now, product can be the compound of following chemical formula 2-1.
[chemical formula 2-1]
In chemical formula, R1And R2It is each independently alkyl；Preferably, described R1And R2Each
Independently be C1-C4Alkyl；It is highly preferred that described R1And R2It can be methyl (methyl).Described chemistry
The compound name of formula 2-1 is 3-(2-alkoxyl-2-oxoethoxy) thiophene-2-carboxylic acid Arrcostab (alkyl
3-(2-alkoxy-2-oxoethoxy)thiophene-2-carboxylate)。
Step (A) can comprise the following steps that (A-1) by the compound of chemical formula 2 in solvent and alkali with change
The compound of formula 3 carries out reaction and obtains product；And (A-2) is anti-by obtain in step (A-1)
Answer product to be hydrolyzed in the alkali of aqueous liquid, prepare the compound of chemical formula 4.The alkali of aqueous liquid
Dispersing or dissolving in water for alkali, the alkali of aqueous liquid has been in the state containing water, thus product
Can be hydrolyzed.
Meanwhile, in the specific embodiment of the present invention, described step (A-1) can include contact procedure (A-1a),
Add for the first time step (A-1b), for the first time whipping step (A-1c), second time adds step (A-1d), the
Secondary stirring (A-1e) and purification step (A-1f).
Contact procedure can be by the compound of solvent and chemical formula 2 at 15 DEG C～30 DEG C, preferably exist
Carry out contacting to obtain the step of product of contact at 18 DEG C～25 DEG C.Solvent can be but be not limited to non-pole
Property solvent, such as, dimethylformamide, dichloromethane, benzene, toluene, four chloromethanes, ether,
Diisopropyl ether and/or dimethyl sulfoxide etc..
Adding step for the first time can be at 15 DEG C～30 DEG C, preferably at 18 DEG C～25 DEG C, by alkali
Add in the product of contact obtained to contact procedure to obtain the step of affixture.Alkali can be but also
It is not limited to, such as, K2CO3、Na2CO3, KOH and/or NaOH etc..
Whipping step can be at 35 DEG C～45 DEG C, preferably at 38 DEG C～42 DEG C for the first time, by
Once add the affixture obtained in step and be stirred obtaining the step of the first stirring product.First
Stirring in secondary whipping step can carry out 20 minutes～50 minutes.
After second time interpolation step can be by first time whipping step, the compound of chemical formula 3 is added
Add in the first stirring product to obtain the step of affixture.
After whipping step can be by adding step for the second time for the second time, at 80 DEG C～100 DEG C, preferably
Second stirring product, at 88 DEG C～93 DEG C, is stirred obtaining the final step stirring product by ground,
The i.e. parent material of the compound by chemical formula 2 is made to generate the compound of chemical formula 2-1.After completing stirring,
Add water and obtain white solid.Stirring in whipping step for the second time can be carried out 1.5 hours～4 hours, excellent
Selection of land can carry out 1.5 hours～2 hours.
Described final stirring product can refine the compound of chemical formula 2-1 through purification step.Purification step can
Including with solvent by finally stir product carry out extraction obtain extraction product extraction step；And will extraction
Extraction product in step carries out concentrating the concentration step obtaining enriched product.Can by described purification step
Prepare the compound of the chemical formula 2-1 of higher purity.
Extraction step is with solvent, stirring product to be carried out extraction to obtain the step of extraction product.Specifically,
Stirring product is carried out extraction and obtains solvent layer by available solvent, washes the methods such as solvent layer with water.Solvent can
Be not limited to non-polar solven to be, such as, dimethylformamide, dichloromethane, benzene, toluene,
Four chloromethanes, ether, diisopropyl ether and/or dimethyl sulfoxide etc..Concentration step is for use anhydrous MgSO4
Remove the water contained in extraction product, remove solvent with rotary concentrator, concentrated acquisition enriched product
Step.
Meanwhile, in a particular embodiment of the present invention, described step (A-2) can include add step (A-2a),
Step (A-2c) is added in whipping step (A-2b) and acid.
Adding step can be at 15 DEG C～30 DEG C, preferably at 18 DEG C～25 DEG C, by aqueous liquid
Alkali add in the product of step (A-1) to obtain the step of affixture.Alkali can be but not
It is limited to, such as, NaOH, Na2CO3, KOH and/or K2CO3Deng.
Whipping step can be at 70 DEG C～90 DEG C, preferably at 75 DEG C～80 DEG C, will add step
In affixture be stirred with obtain stirring product step.Whipping step can be carried out 30 minutes～2
Hour.
It can be that acid is added the step carrying out being acidified to stirring product that step is added in acid.Such as, acid adds
Add step can be by stirring product temperature be down to-10 DEG C～0 DEG C after, add acid to pH value be the step of 1
Suddenly.Described acid can be the material of regulation pH value, but is not limited to, such as, and hydrochloric acid, nitric acid, sulfur
Acid and/or acetic acid etc..
Disposably can prepare the compound of chemical formula 4 of 500g～5000g by high yield by the way.
Step (B)
Step (B) is for carry out monoalkylation in a solvent by the compound of chemical formula 4
(monoalkylation) step of compound in chemical formula 5 is prepared.Such as, by contact procedure (Ba),
Dropping step (Bb), whipping step (Bc) and purification step (Bd), prepared by the compound of chemical formula 4
The compound of chemical formula 5.
Contact procedure can be at 0 DEG C～10 DEG C, selection of land at 0 DEG C～5 DEG C, by solvent and chemical formula 4
Compound carry out contacting to obtain the step of product of contact.Solvent can be but to be not limited to polarity molten
Agent, such as, methanol, isopropanol and/or butanol etc..
Dropping step can be at 0 DEG C～10 DEG C, preferably at 4 DEG C～8 DEG C, by sulphuric acid (H2SO4)
Drop in the product of contact in contact procedure to obtain the step of dropping product.
Whipping step can be at 10 DEG C～30 DEG C, is stirred by the dropping product in dropping step
Step, mixing time is 2 hours～6 hours, it is therefore preferable to 2 hours～3 hours.This step is for obtaining
The final step stirring product, is generated the chemical combination of chemical formula 5 by the i.e. parent material of compound of chemical formula 4
Thing.
Purification step can include filter stirring the filtration step of product, extraction step, concentration step and
Drying steps.The compound of the chemical formula 5 of higher purity can be prepared by described purification step.
Specifically, described filtration step can obtain filtration product by filtering stirring product.In detail,
The sides such as stirring product is carried out filtering acquisition filtration product by available filter paper, the solids washed with water after filtration
Method.
Water after washing can be used for using solvent-extracted extraction step.Solvent can be but be not limited to non-pole
Property solvent, such as, dimethylformamide, dichloromethane, benzene, toluene, four chloromethanes, ether,
Diisopropyl ether and/or dimethyl sulfoxide etc..
Concentration step can remove solvent, concentrated acquisition enriched product with rotary concentrator.
Meanwhile, by the filtration product in described filtration step and enriched product can be done after merging
Dry.
Disposably can prepare the compound of chemical formula 5 of 500g～5000g by high yield by the way.
Step (C)
Step (C) is for be heated to 80 DEG C～300 DEG C under solvent free conditions by the compound of chemical formula 5
Carry out the step of decarboxylic reaction (decarboxylation).
In a kind of detailed description of the invention, step (C) passes through heating steps by the compound system of chemical formula 5
Obtain the compound of chemical formula 1.
In heating steps, under conditions of there is no specific solvent, only the compound of chemical formula 5 is heated
To 80 DEG C～300 DEG C, preferably to 160 DEG C～240 DEG C, carry out 6 hours～48 hours.But it is not limited to
This.This step is the step obtaining end product, the compound of chemical formula 5 generate chemical formula 1
Compound.
Disposably the compound of chemical formula 1 of 500g～5000g can be prepared by high yield by described mode.
And then, pass through one embodiment of the present invention, it is possible to provide one embodiment of the present invention of generation
The 3-alkoxy thiophene derivant of chemical formula 1.
Hereinafter, the embodiment 1 of the preparation method of each step is included by the explanation of a kind of embodiment
To embodiment 4.Wherein, embodiment 1 is a kind of embodiment of the parent material preparing embodiment 2.
Embodiments of the present invention and the change of the prepared present invention thereof are further described by specific embodiment
The 3-alkoxy thiophene derivant of formula 1.
<embodiment 1>prepares 3-hydroxy thiophene-2-carboxylate methyl ester (methyl
3-hydroxythiophene-2-carboxylate)
Embodiment 1 is further described by reference reaction formula 1-1.
[reaction equation 1-1]
Two mouthfuls of flasks of 250ml arrange thermometer and addition funnel, cools down with frozen water
(-10 DEG C～0 DEG C).Put 30ml absolute methanol and the 0.8g metallic sodium being cut into small pieces into flask, be passed through nitrogen
Gas is sealed against.
When internal temperature to 0 DEG C, the 2.4g 2-methyl thioglycolate of 20ml methanol will be completely dissolved in
(methyl 2-mercaptoacetate, Sigma-Aldrich) puts in addition funnel lentamente
Drip.
After completing dropping, the 3.5g 2-chloracrylic acid ethyl ester (ethyl of 20ml methanol will be completely dissolved in
2-chloroacrylate, Sigma-Aldrich) put in addition funnel and drip lentamente.
After completing dropping, removing cooling water, at room temperature (18 DEG C～26 DEG C) stir 2 hours.Now
Form yellow solid.
Methanol in volatilization stirring product, concentrates, and being acidified to pH value with 4N hydrochloric acid is 2.After being acidified
Product dchloromethane, every time with 30ml, extract 3 times, after collection organic solvent layer
Wash three times.Organic solvent layer is separated, puts into anhydrous magnesium sulfate, place and be dried for 20 minutes.
Afterwards, it is filtered to remove anhydrous magnesium sulfate, then from residue, removes organic solvent with rotary concentrator and enter
Row concentrates.Yellow oil product is obtained with this.By the oil product that obtained by the method at normal hexane and
In ethyl acetate mixture (normal hexane: ethyl acetate=20:1), crystallization obtains pale yellow crystals.Yield is
68%.
<embodiment 2>prepares 3-(Carboxvmethoxv) thiophene-2-carboxylic acid
(3-(carboxymethoxy)thiophene-2-carboxylic acid)
Embodiment 2 is further described by reference reaction formula 2-A.
[reaction equation 2-A]
250ml there-necked flask arranges thermometer and cooler.At room temperature (18 DEG C～25 DEG C), will
1.38g 3-hydroxy thiophene-2-carboxylate methyl ester (methyl 3-hydroxythiophene-2-carboxylate) is put
Enter flask to be dissolved in 20ml dimethylformamide.
The K of 1.2g is put in solute2CO3At room temperature (18 DEG C～25 DEG C) stir 10 minutes.
Solid K is left when being stirred2CO3。
Stir 30 minutes at 40 DEG C after oil bath is set.Afterwards, the 2-bromoacetic acid of 1.4g is disposably put into
Methyl ester (methyl 2-bromoacetate), is stirred after temperature rises to 90 DEG C.Reacted about 2
After hour, add water to flask and obtain white solid.
Confirm that reaction carries out completely by TLC, extract 3 times with dichloromethane, every time with 50ml, receive
Collection organic solvent layer.Organic solvent layer is washed with water 3 times, use 50ml every time.By organic solvent layer
Separate, put into anhydrous magnesium sulfate, place and be dried for 20 minutes.Then, it is filtered to remove anhydrous slufuric acid
After magnesium, from residue, remove organic solvent with rotary concentrator and concentrate.
2.3g 3-(2-methoxyl group-2-oxoethoxy) thiophene-2-carboxylic acid methyl ester (methyl is obtained with this
3-(2-methoxy-2-oxoethoxy) thiophene-2-carboxylate), yield is 87%.NMR data
As follows:
1H-NMR(300MHz,CDCl3)δ3.92(s,3H),6.78(d,1H),7.28(d,1H)
Then, at room temperature (18 DEG C～25 DEG C) are by the 3-(2-methoxyl group-2-oxoethoxy) of 2.3g
Thiophene-2-carboxylic acid methyl ester is put in 250ml flask, puts into the 1M NaOH solution of 40ml, by temperature
Rise to 90 DEG C, return stirring 1 hour.Reaction liquid frozen water cools down (-10 DEG C～0 DEG C), is acidified with hydrochloric acid
To pH=1.
Result obtains 3-(Carboxvmethoxv) thiophene-2-carboxylic acid of white solid, and yield is 93%.NMR
Data are as follows:
1H-NMR(400MHz,DMSO)δ4.75(s,2H),6.90(d,1H),7.67(d,1H)
<embodiment 3>prepares 3-(2-methoxyl group-2-oxoethoxy) thiophene-2-carboxylic acid
(3-(2-methoxy-2-oxoethoxy)thiophene-2-carboxylic acid)
Embodiment 3 is further described by reference reaction formula 2-B.
[reaction equation 2-B]
2000ml there-necked flask arranges agitator, thermometer and addition funnel, carries out cold with frozen water
But.By 3-(Carboxvmethoxv) thiophene-2-carboxylic acid of 1500ml methanol and 100g
(3-(carboxymethoxy) thiophene-2-carboxylic acid) puts in flask.Now temperature is protected
Hold at 4 DEG C.
37.5ml sulphuric acid is put in addition funnel and drips lentamente.Now temperature is maintained at
4 DEG C～8 DEG C.
After completing dropping, removing cooling water, at room temperature (15 DEG C～25 DEG C) are stirred.About 3 is little
Shi Houyong TLC confirms whether react complete as 3-(Carboxvmethoxv) thiophene-2-carboxylic acid of parent material.
After confirming reaction completely with TLC, filter with filter paper.
The solids washed with water 5 times filtered, the most about with 20～30ml, with infrared drying 1 day.
Residual solution is put in 2000ml flask, after concentrated solvent, by its solids washed with water 5 times,
Every time the most about with 100ml, with infrared drying 1 day.
Water after washing is collected, after dichloromethane extraction, concentrating, by its solids washed with water 5 times,
Every time the most about with 100ml, with infrared drying 1 day.
Weigh after dried solid is collected.Result obtains about 97g brown solid, and yield is 90%.
NMR data is as follows:
1H-NMR(400MHz,DMSO)δ3.65(s,3H),4.88(s,2H),6.93(d,1H),
7.68(d,1H)
<embodiment 4>prepares 2-(thiophene-3-epoxide) methyl acetate (methyl
2-(thiophene-3-yloxy)acetate)
Embodiment 4 is further described by reference reaction formula 2-C.
[reaction equation 2-C]
By 3-(2-methoxyl group-2-oxoethoxy) thiophene-2-carboxylic acid of 244g
(3-(2-methoxy-2-oxoethoxy) thiophene-2-carboxylic acid) puts into 2000ml tri-mouthfuls burning
In Ping, agitator, thermometer, cooler and oil bath are set, are heated to 230 DEG C.
Time between temperature about 180 DEG C～200 DEG C, solid begins to change into liquid, in temperature about
Start to generate gas time between 210 DEG C～230 DEG C.
Reaction temperature falls to approximately 165 DEG C～168 DEG C after rising to 230 DEG C.
After about 6 hours, confirm the 3-(2-methoxyl group-2-oxoethoxy) as parent material with TLC
Thiophene-2-carboxylic acid (3-(2-methoxy-2-oxoethoxy) thiophene-2-carboxylic acid) is the most anti-
Should be complete.
As confirmed, parent material still has residual, then further stir about 3 hours.
After confirming reaction completely with TLC, withdraw from oil bath, reclaim after Slow cooling and generate product.
Result obtains 177g brown liquid.Yield is 91%.NMR data is as follows:
1H-NMR(400MHz,CDCl3)δ3.73(s,3H),4.53(s,2H),6.21(s,1H),6.77(d,1H),
7.13(d,1H)。
Claims (20)
1. a preparation method for the 3-alkoxy thiophene derivant of following chemical formula 1, the method includes
Following steps:
(A) compound of the compound of following chemical formula 2 Yu following chemical formula 3 is carried out reaction and obtains anti-
After answering product, the hydrolysis of described product is prepared the compound of following chemical formula 4；
(B) compound of prepared chemical formula 4 is carried out monoalkylation in a solvent, prepare following
The compound of chemical formula 5；And
(C) compound of prepared chemical formula 5 is heated to 80 DEG C～300 under solvent free conditions
DEG C carry out decarboxylic reaction；
In chemical formula, R1And R2Being each independently alkyl, X is halogen.
Preparation method the most according to claim 1, wherein, described R1And R2Independently of one another
For C1-C4Alkyl.
Preparation method the most according to claim 1, wherein, described R1And R2For methyl.
Preparation method the most according to claim 1, wherein, described X is bromine.
Preparation method the most according to claim 1, wherein, under the product in step (A) is
State the compound of chemical formula 2-1；
In chemical formula, R1And R2It is each independently alkyl.
Preparation method the most according to claim 1, wherein, step (A) comprises the following steps:
(A-1) by the compound of described chemical formula 2 in solvent and alkali with the compound of described chemical formula 3
Carry out reaction and obtain product；And
(A-2) product obtained in step (A-1) is hydrolyzed in the alkali of aqueous liquid, prepares
The compound of described chemical formula 4.
Preparation method the most according to claim 6, wherein, step (A-1) comprises the following steps:
(A-1a) at 15 DEG C～30 DEG C, the compound of solvent with described chemical formula 2 is contacted, with
Obtain the contact procedure of product of contact；
(A-1b) at 15 DEG C～30 DEG C, alkali is added in the product of contact obtained to step (A-1a),
To obtain the first time interpolation step of affixture；
(A-1c) at 35 DEG C～45 DEG C, the affixture obtained in step (A-1b) is stirred, with
Obtain the first time whipping step of the first stirring product；
(A-1d) in described first stirring product, the compound of described chemical formula 3 is added, to obtain interpolation
The second time of product adds step；
(A-1e) at 80 DEG C～100 DEG C, the second time of step (A-1d) is added the interpolation product that step obtains
Thing is stirred, to obtain the second time whipping step of the second stirring product；And
(A-1f) the second stirring product non-polar solven in step (A-1e) is carried out extraction and obtain extraction product
After thing, described extraction product is concentrated, to obtain the purification step of enriched product.
Preparation method the most according to claim 6, wherein, the solvent in step (A-1) is selected from two
Methylformamide, dichloromethane, benzene, toluene, four chloromethanes, ether, diisopropyl ether and dimethyl
One or more non-polar solvens in sulfoxide.
Preparation method the most according to claim 6, wherein, the alkali in step (A-1) is selected from K2CO3、
Na2CO3, one or more in KOH and NaOH.
Preparation method the most according to claim 6, wherein, step (A-2) comprises the following steps:
(A-2a) at 15 DEG C～30 DEG C, the product of step (A-1) is added the alkali of aqueous liquid,
To obtain the interpolation step of affixture；
(A-2b) at 70 DEG C～90 DEG C, the affixture that step (A-2a) obtains is stirred, to obtain
The whipping step of product must be stirred；And
(A-2c) in the stirring product of step (A-2b), add the step of acid.
11. preparation methoies according to claim 10, wherein, step (A-2c) is by step (A-2b)
Stirring product at a temperature of be adjusted to-10 DEG C～0 DEG C after to add described acid to pH value be 1.
12. according to the preparation method described in claim 10 or 11, wherein, and the acid in step (A-2c)
For hydrochloric acid, nitric acid, sulphuric acid or acetic acid.
13. preparation methoies according to claim 1, wherein, step (B) comprises the following steps:
(Ba) at 0 DEG C～10 DEG C, the compound of solvent with chemical formula 4 is contacted, connect to obtain
Touch the contact procedure of product；
(Bb) at 0 DEG C～10 DEG C, the product of contact of step (Ba) drips sulphuric acid, to obtain dropping
The dropping step of product；
(Bc) at 10 DEG C～30 DEG C, the dropping product of step (Bb) is stirred 2 hours～6 hours, to obtain
The whipping step of product must be stirred；And
(Bd) described stirring product is carried out the purification step refined.
14. preparation methoies according to claim 13, wherein, the solvent in step (Ba) is selected from
One or more polar solvents in methanol, isopropanol and butanol.
15. preparation methoies according to claim 13, wherein, refined in step (Bd) includes
Filtration step, extraction step, concentration step and drying steps.
16. preparation methoies according to claim 1, wherein, step (C) is at 160 DEG C～240 DEG C
Carry out.
17. preparation methoies according to claim 1, wherein, step (C) is carried out 6 hours～48 little
Time.
18. preparation methoies according to claim 1, wherein, the method also includes described chemical formula
The preparation of the compound of 2, it comprises the following steps:
A solvent, at-10 DEG C～5 DEG C, is contacted by () with metallic sodium, to obtain the contact of product of contact
Step；
B (), at-10 DEG C～10 DEG C, the contact that the compound of following chemical formula 6 drops to step (a) is produced
In thing, to obtain the first time dropping step of the first dropping product；
C the compound of following chemical formula 7, at-10 DEG C～10 DEG C, is dropped to acquisition in step (b) by ()
In first dropping product, it is thus achieved that the second time dropping step of the second dropping product；
D obtain in step (c) second dropping product, at 15 DEG C～30 DEG C, is stirred, to obtain by ()
Obtain the whipping step finally stirring product；
E () adds acid, to obtain the step of affixture in described final stirring product；And
F the affixture obtained in step (e) is carried out the purification step extracting and concentrating by (), thus prepare
The compound of described chemical formula 2；
In chemical formula, R2For alkyl.
19. preparation methoies according to claim 18, wherein, the extraction in step (f) uses choosing
From dimethylformamide, dichloromethane, benzene, toluene, four chloromethanes, ether, diisopropyl ether and two
One or more non-polar solvens in methyl sulfoxide.
20. 1 kinds of 3-alkoxy thiophene derivants, this 3-alkoxy thiophene derivant is according to claim
The 3-alkoxy thiophene derivant of the chemical formula 1 that the preparation method described in 1 obtains.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954976A (en) * | 2017-12-08 | 2018-04-24 | 贝利化学（张家港）有限公司 | A kind of method of synthesis 3,4- dimethoxy-thiophenes |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258053A (en) * | 1975-06-05 | 1981-03-24 | Hoechst Aktiengesellschaft | Thienyl-prostaglandins and process for their manufacture |
| US4352819A (en) * | 1980-11-28 | 1982-10-05 | Laevosan-Gesellschaft Mbh & Co. Kg | Novel 1-[3-(2-hydroxy-3-alkylaminopropoxy)-2-thienyl]-3-phenyl-1-propanones and their salts and a process for the preparation thereof |
-
2015
- 2015-03-30 CN CN201510144057.3A patent/CN106146455A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4258053A (en) * | 1975-06-05 | 1981-03-24 | Hoechst Aktiengesellschaft | Thienyl-prostaglandins and process for their manufacture |
| US4352819A (en) * | 1980-11-28 | 1982-10-05 | Laevosan-Gesellschaft Mbh & Co. Kg | Novel 1-[3-(2-hydroxy-3-alkylaminopropoxy)-2-thienyl]-3-phenyl-1-propanones and their salts and a process for the preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| CORRAL, C. ET AL.: "Reactions with 3-hydroxy-2-methoxycarbonylthiophene; I. Synthesis of 3-Tienyloxyacetic Acid and its (Nuclear) Chloro and Bromo Derivatives", 《SYNTHESIS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107954976A (en) * | 2017-12-08 | 2018-04-24 | 贝利化学（张家港）有限公司 | A kind of method of synthesis 3,4- dimethoxy-thiophenes |
| CN107954976B (en) * | 2017-12-08 | 2019-05-31 | 贝利化学（张家港）有限公司 | A method of synthesis 3,4- dimethoxy-thiophene |
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