CN109265437A - A kind of preparation method of 3- hydroxy thiophene -2- carboxylic acid ester compound - Google Patents
A kind of preparation method of 3- hydroxy thiophene -2- carboxylic acid ester compound Download PDFInfo
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- CN109265437A CN109265437A CN201811224516.9A CN201811224516A CN109265437A CN 109265437 A CN109265437 A CN 109265437A CN 201811224516 A CN201811224516 A CN 201811224516A CN 109265437 A CN109265437 A CN 109265437A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
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Abstract
The present invention provides a kind of preparation methods of 3- hydroxy thiophene -2- carboxylic acid ester compound.The preparation method includes: to makeIt carries out condensation reaction under alkaline condition with E-3- methoxy-methyl acrylate and forms 3- hydroxy thiophene -2- carboxylic acid ester compound, wherein any one in the alkenyl of alkyl of the R selected from C1~C10, C2~C10.Using
Description
Technical field
The present invention relates to the synthesis fields of pharmaceutical intermediate, in particular to a kind of 3- hydroxy thiophene -2- carboxylic acid esters
The preparation method of compound.
Background technique
3- hydroxy thiophene -2- carboxylate methyl ester is the important medicine of one kind, pesticide intermediate, the at present main conjunction of the compound
Have at method:
Preparation 3- hydroxyl thiophene is reacted under the conditions of sodium methoxide/methanol using 2- chloracrylic acid methyl esters and methyl thioglycolate
Pheno -2- carboxylate methyl ester, yield 70%.The raw material 2- chloracrylic acid methyl esters that this method uses is expensive, and more difficult preparation, causes
This method higher cost.
Preparation 3- hydroxy thiophene -2- is reacted under the conditions of sodium methoxide/methanol using Methyl propiolate and methyl thioglycolate
Carboxylate methyl ester, yield 70%.But the raw material Methyl propiolate that this method uses is expensive, causes the route higher cost.
These methods of the prior art can not be precisely controlled reaction by serialization and prepare 3- hydroxy thiophene -2- carboxylic acid first
Ester, and then said synthesis route is caused all to be unable to satisfy economic, effective, safety preparation 3- hydroxy thiophene -2- carboxylic acid first
The requirement of ester.
Summary of the invention
The main purpose of the present invention is to provide a kind of preparation method of 3- hydroxy thiophene -2- carboxylic acid ester compound, with
Solve the problems, such as that 3- hydroxy thiophene -2- carboxylate methyl ester synthesis cost is high in the prior art.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of 3- hydroxy thiophene -2- carboxylic acid esters
The preparation method of compound, comprising: makeIt contracts under alkaline condition with E-3- methoxy-methyl acrylate
It closes reaction and forms 3- hydroxy thiophene -2- carboxylic acid ester compound, wherein in the alkenyl of alkyl of the R selected from C1~C10, C2~C10
Any one.
Further, above-mentioned R is selected from-CH3、-C2H5、-C3H8、-C4H10、-C5H12、-C6H14、-C7H16、-C8H18、-CH
(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH(CH3)(C2H5)、-CH2CH=CH2、 In any one.
Further, above-mentioned preparation method include: byIt is mixed with the first solvent, forms the first raw material
Liquid；E-3- methoxy-methyl acrylate is mixed with the second solvent, forms the second material liquid；By the first material liquid, the second raw material
Liquid and alkaline conditioner are continuously passed through in continuous reaction device and carry out serialization condensation reaction, form 3- hydroxy thiophene -2- carboxylic
Acid esters compound.
Further, above-mentioned first solvent and the second solvent are each independently selected from water, methanol, ethyl alcohol, isopropanol, tertiary fourth
Alcohol, n-butanol, chloroform, methylene chloride, ethyl acetate, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tetrahydrofuran, 2- first
Base tetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N, N- dimethyl
Formamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide and acetonitrile composition
Group in any one or more.
Further, above-mentioned alkaline conditioner is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tert-butylamine, triethylene diamine, diazabicylo, KOH, NaOH,
K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3, sodium acetate composition group in any one or more.
Further, above-mentionedMolar ratio with E-3- methoxy-methyl acrylate is 1:1~3:1, excellent
It is selected as 1.5:1~2.5:1, the molar ratio of E-3- methoxy-methyl acrylate and alkaline conditioner is 1:5~1:1, preferably 1:
3.5~1:2.5.
Further, above-mentioned serialization condensation reaction carries out at 0~200 DEG C, preferably carries out at 50~150 DEG C.
Further, above-mentioned serialization condensation reaction carries out under the pressure of 1~2MPa, preferably serialization condensation reaction
Retention time is 30~120min.
Further, above-mentioned preparation method further include: serialization condensation reaction is obtained using hydrogen chloride/methanol solution
System is quenched at 0~10 DEG C, obtains that system is quenched；The system of being quenched is purified, 3- hydroxy thiophene -2- carboxylic acid is obtained
Ester type compound.
Further, above-mentioned purification includes: to carry out the system of being quenched to be concentrated under reduced pressure to give residue and methanol；By residue
It is evaporated under reduced pressure, obtains 3- hydroxy thiophene -2- carboxylic acid ester compound.
It applies the technical scheme of the present invention, the application usesIt is original with E-3- methoxy-methyl acrylate
Material makes the two carry out condensation reaction under alkaline condition and forms thiphene ring, and above-mentioned reaction is easy to carry out, the easy control of reaction condition
It makes, the product yield under felicity condition is higher.Above-mentioned E-3- methoxy-methyl acrylate relative to 2- chloracrylic acid methyl esters or
Cost is relatively low for Methyl propiolate, therefore reduces the synthesis technology cost of 3- hydroxy thiophene -2- carboxylic acid ester compound.
Specific embodiment
It should be noted that in the absence of conflict, the features in the embodiments and the embodiments of the present application can phase
Mutually combination.Below in conjunction with embodiment, the present invention will be described in detail.
The analysis as described in the application background technique, the synthesis of 3- hydroxy thiophene -2- carboxylate methyl ester in the prior art is former
Expect higher cost, leads to synthetic route higher cost.In order to solve this problem, this application provides a kind of 3- hydroxy thiophene -2-
The preparation method of carboxylic acid ester compound, the preparation method include: to makeWith E-3- methoxy-methyl acrylate
Condensation reaction is carried out under alkaline condition and forms 3- hydroxy thiophene -2- carboxylic acid ester compound, and wherein R is selected from the alkane of C1~C10
Base, C2~C10 alkenyl in any one.
The application usesIt is raw material with E-3- methoxy-methyl acrylate, makes the two under alkaline condition
It carries out condensation reaction and forms thiphene ring, above-mentioned reaction is easy to carry out, easy control of reaction conditions, the product yield under felicity condition
It is higher.Cost is relatively low relative to 2- chloracrylic acid methyl esters or Methyl propiolate for above-mentioned E-3- methoxy-methyl acrylate, because
This reduces the synthesis technology cost of 3- hydroxy thiophene -2- carboxylic acid ester compound.
Above-mentioned preparation method can be used for the preparation of a variety of 3- hydroxy thiophene -2- carboxylic acid ester compounds, preferably above-mentioned R choosing
From-CH3、-C2H5、-C3H8、-C4H10、-C5H12、-C6H14、-C7H16、-C8H18、-CH(CH3)2、-C(CH3)3、-CH2CH
(CH3)2、-CH(CH3)(C2H5)、-CH2CH=CH2、 In any one.It is above-mentioned eachChemically
It can stablize, reactivity is higher.
In a preferred embodiment of the present application, above-mentioned preparation method include: byWith the first solvent
Mixing forms the first material liquid；E-3- methoxy-methyl acrylate is mixed with the second solvent, forms the second material liquid；By
One material liquid, the second material liquid and alkaline conditioner are continuously passed through in continuous reaction device and carry out serialization condensation reaction, shape
At 3- hydroxy thiophene -2- carboxylic acid ester compound.
By using serialization equipment, reaction rate is greatly improved, reduces the generation of by-product, thus further
Improve product yield；The distinctive rate of heat exchange of serialization equipment allows reaction condition more much higher than batch equipment attribute
Acutely, it is realized in high yield under the premise of ensure that reaction safety；Above-mentioned preparation method has continuous process particular attribute,
Almost without enlarge-effect in production, industrialization is suitble to reappear lab scale yield.
Above-mentioned continuous reaction device can be using conventional continuous reaction device, such as continuous coil pipe, continuous CSTR etc. even
Continuous reactor.It is anti-that above-mentioned first material liquid, the second material liquid and alkaline conditioner by feed pump uninterrupted pumping enter serialization
Answer progress serialization condensation reaction in device.
Above-mentioned first solvent and the second solvent are for dispersing reaction raw materials, and the serialization for being conducive to reaction raw materials is defeated
Enter, as long as therefore can be realized the atent solvent of above-mentioned effect and be contemplated that applied to the application, be based on this, preferably above-mentioned first
Solvent and the second solvent be each independently selected from water, methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, chloroform, methylene chloride,
Ethyl acetate, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane,
Glycol dimethyl ether, diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide,
N, N- diethylformamide, N-Methyl pyrrolidone, dimethyl sulfoxide and acetonitrile composition group in any one or more.
Alkaline environment needed for the alkaline conditioner of the application is used to provide reaction, preferably alkaline conditioner are selected from methanol
Sodium, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tertiary fourth
Amine, triethylene diamine (DABCO), diazabicylo (DBU), KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3、
Sodium acetate composition group in any one or more.In addition, the solubility of organic above-mentioned alkaline conditioner in organic solvent
Difference can most preferably dissolve highly basic in organic solvent to reduce the dosage of alkaline conditioner, and effect is best, such as
Sodium alkoxide class；Alkali in organic solvent, such as organic amine can followed by be dissolved.Its dosage is to be capable of forming alkaline environment
Subject to, it is preferably able to adjust the pH value of the reaction system in flow reactor between 8~14.
In order to react each reaction raw materials sufficiently, its conversion ratio is improved, it is preferably above-mentionedWith E-3- methoxy
The molar ratio of base methyl acrylate is 1:1~3:1, preferably 1.5:1~2.5:1, E-3- methoxy-methyl acrylate and alkalinity
The molar ratio of regulator is 1:5~1:1, preferably 1:3.5~1:2.5.The group that above-mentioned molar ratio passes through the first material liquid of control
Liquid is adjusted at the charging rate of the, composition of the second material liquid and the first material liquid, the charging rate of the second material liquid, alkalinity
Charging rate is adjusted, and specific regulative mode those skilled in the art can be realized by routine test means, herein not
It repeats again.
The above-mentioned preparation method of the application can carry out at normal temperature, can also carry out at high temperature, preferably above-mentioned continuous
Change condensation reaction to carry out at 0~200 DEG C, temperature is higher within the above range, and reaction rate is faster, but required thermal energy is higher；
Yield is improved in order to reduce cost, is preferably carried out at 50~150 DEG C.
The continuous reaction of the application carries out in continuous reaction equipment, and high temperature and pressure may be implemented, and the pressure the high right
The resistance to pressure of equipment requires higher equipment cost higher, excellent in order to reduce equipment cost under the premise of realizing high reaction rate
It chooses and states serialization condensation reaction and carried out under the pressure of 1~2MPa.
In addition, by verification experimental verification, yield can also be increased by being appropriately extended the reaction time, preferably serialization condensation reaction
Retention time is 30~120min.
In the application another kind preferred embodiment, above-mentioned preparation method further include: utilize hydrogen chloride/methanol solution pair
The system that serialization condensation reaction obtains is quenched at 0~10 DEG C, obtains that system is quenched；The system of being quenched is purified,
Obtain 3- hydroxy thiophene -2- carboxylic acid ester compound.It is above-mentioned that process is quenched is simply easily operated.
Further, since the application products obtained therefrom yield is higher, therefore its purification process can also be carried out using various ways,
It is preferred that above-mentioned purification includes: to carry out the system of being quenched to be concentrated under reduced pressure to give residue and methanol；Residue is evaporated under reduced pressure,
Obtain 3- hydroxy thiophene -2- carboxylic acid ester compound.Above-mentioned reduced pressure and vacuum distillation are this field common process, therefore
Be conducive to popularization and application of the preparation method of the application under existence conditions.
Below with reference to embodiment and comparative example, the beneficial effect of the application is further illustrated.
Embodiment 1
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set dnockout bottle charging rate as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 60.1g of net product white solid by cooling after vacuum distillation,
Purity 99.5%, yield 88.2%.
Above-mentioned white solid product is detected by nuclear-magnetism and high resolution mass spectrum, and testing result is as follows:
1H NMR(500MHz,CDCl3) δ: 7.37 (d, J=5.5Hz, 1H), 6.74 (d, J=5.5Hz, 1H), 3.89 (s,
3H)。
HRMS(ESI)m/z[M+H]+Calcd for C6H6O3S 158.1750,found 158.1743。
Embodiment 2
The flow reactor of dried and clean is heated to 150 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 55.3g of net product white solid by cooling after vacuum distillation,
Purity 99.1%, yield 81.2%.
Embodiment 3
The flow reactor of dried and clean is heated to 50 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 24.8g of net product white solid by cooling after vacuum distillation,
Purity 98.4%, yield 36.4%.
Embodiment 4
The flow reactor of dried and clean is heated to 30 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 20.2g of net product white solid by cooling after vacuum distillation,
Purity 96.1%, yield 29.7%.
Embodiment 5
The flow reactor of dried and clean is heated to 200 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 15.7g of net product white solid by cooling after vacuum distillation,
Purity 98.6%, yield 23.1%.
Embodiment 6
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (50.3g, 0.47mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 12.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 58.7g of net product white solid by cooling after vacuum distillation,
Purity 98.9%, yield 43.3%.
Embodiment 7
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (70g, 0.65mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set dnockout bottle charging rate as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 54.6g of net product white solid by cooling after vacuum distillation,
Purity 99.1%, yield 80.2%.
Embodiment 8
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (115g, 1.07mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set dnockout bottle charging rate as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 59.4g of net product white solid by cooling after vacuum distillation,
Purity 99.3%, yield 87.2%.
Embodiment 9
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (137.1g, 1.29mol) and first
Alcohol (150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-
3- methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Degree starts dnockout after stablizing, and sets 1 charging rate of dnockout bottle as 8.77g/min, sets the charging rate of dnockout bottle 2 as 0.55g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 58.7g of net product white solid by cooling after vacuum distillation,
Purity 98.9%, yield 86.2%.
Embodiment 10
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (77.6g, 0.43mol) to be placed in dnockout bottle 2, is taken E-3- first
Oxygroup methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.It is steady to continuous coil reactor temperature
Start dnockout after fixed, sets 1 charging rate of dnockout bottle as 10.57g/min, set the charging rate of dnockout bottle 2 as 0.18g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 12.5g of net product white solid by cooling after vacuum distillation,
Purity 99.1%, yield 18.4%.
Embodiment 11
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (194g, 1.075mol) to be placed in dnockout bottle 2, is taken E-3- first
Oxygroup methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.It is steady to continuous coil reactor temperature
Start dnockout after fixed, sets 1 charging rate of dnockout bottle as 10.57g/min, set the charging rate of dnockout bottle 2 as 0.18g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 57.1g of net product white solid by cooling after vacuum distillation,
Purity 98.9%, yield 83.8%.
Embodiment 12
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (271.6g, 1.505mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.18g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 59.0g of net product white solid by cooling after vacuum distillation,
Purity 99.1%, yield 86.6%.
Embodiment 13
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (388.0g, 2.15mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.90g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 59.5g of net product white solid by cooling after vacuum distillation,
Purity 99.2%, yield 87.4%.
Embodiment 14
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken triethylamine (130.5g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3- methoxy acrylic acid
Methyl esters (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.Start to beat after continuous coil reactor temperature is stablized
Material, sets 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 0.30g/min, sets dnockout
The charging rate of bottle 3 is 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control 1.0~
2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.Body after the completion of being quenched
Methanol is concentrated under reduced pressure out in system, and residue obtains the total 11.g of net product white solid, purity by cooling after vacuum distillation
99.1%, yield 18.4%.
Embodiment 15
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and methanol
(150g) is placed in dnockout bottle 1, is taken 12% potassium tert-butoxide t-butanol solution (1206.3g, 1.29mol) to be placed in dnockout bottle 2, is taken
E-3- methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor
Temperature starts dnockout after stablizing, and sets 1 charging rate of dnockout bottle as 10.57g/min, set the charging rate of dnockout bottle 2 as
2.85g/min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, in continuous coil reactor
Voltage-controlled system is in 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.
System after the completion of being quenched is concentrated under reduced pressure out methanol and the tert-butyl alcohol, and to obtain net product white by cooling after vacuum distillation for residue
The total 33.3g of color solid, purity 99.3%, yield 48.9%.
Embodiment 16
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and tetrahydro
Furans (150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken
E-3- methoxy-methyl acrylate (50.0g, 0.43mol) and tetrahydrofuran (150g) are placed in dnockout bottle 3.It is anti-to continuous coil pipe
Start dnockout after answering device temperature to stablize, sets 1 charging rate of dnockout bottle as 10.57g/min, set the charging rate of dnockout bottle 2
For 2.85g/min, the charging rate of dnockout bottle 3 is set as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor
Internal pressure is controlled in 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, quenches in 0~10 DEG C of temperature control
It goes out.Methanol and tetrahydrofuran is concentrated under reduced pressure out in system after the completion of being quenched, and residue is obtained pure by cooling after vacuum distillation
The total 47.1g of product white solid, purity 98.6%, yield 69.2%.
Embodiment 17
The flow reactor of dried and clean is heated to 100 DEG C.Take methyl thioglycolate (91.4g, 0.86mol) and chloroform
(150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-3-
Methoxy-methyl acrylate (50.0g, 0.43mol) and chloroform (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Start dnockout after stabilization, set 1 charging rate of dnockout bottle as 10.57g/min, sets the charging rate of dnockout bottle 2 as 2.85g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol and chloroform is concentrated under reduced pressure out in system after, and residue is total to by the net product white solid that obtains cooling after vacuum distillation
47.1g, purity 98.6%, yield 69.2%.
Embodiment 18
The flow reactor of dried and clean is heated to 100 DEG C.Take ethyl thioglycolate (103.3g, 0.86mol) and first
Alcohol (150g) is placed in dnockout bottle 1, is taken 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in dnockout bottle 2, is taken E-
3- methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) are placed in dnockout bottle 3.To continuous coil reactor temperature
Degree starts dnockout after stablizing, and sets 1 charging rate of dnockout bottle as 11.1g/min, sets the charging rate of dnockout bottle 2 as 2.85g/
Min sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil reactor internal pressure control
In 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, is quenched in 0~10 DEG C of temperature control.It has been quenched
Methanol is concentrated under reduced pressure out in system after, and residue obtains the total 58.2g of net product white solid by cooling after vacuum distillation,
Purity 98.1%, yield 78.5%.
Above-mentioned white solid product is detected by nuclear-magnetism and high resolution mass spectrum, and testing result is as follows:
1H NMR(500MHz,CDCl3) δ: 7.40 (d, J=5.5Hz, 1H), 6.71 (d, J=5.5Hz, 1H), 4.30 (q,
J=6.0Hz, 2H), 1.29 (t, J=6.0Hz, 3H)
HRMS(ESI)m/z[M+H]+Calcd for C7H8O3S 172.2016,found 172.1993.
Embodiment 19
The flow reactor of dried and clean is heated to 100 DEG C.Take thioacetic acid (2- methacrylic) ester (125.7g,
It 0.86mol) is placed in dnockout bottle 1 with methanol (150g), takes 30% methanol solution of sodium methylate (232.7g, 1.29mol) to be placed in and beat
Expect to take E-3- methoxy-methyl acrylate (50.0g, 0.43mol) and methanol (150g) to be placed in dnockout bottle 3 in bottle 2.To continuous
Coil reactor temperature starts dnockout after stablizing, and sets 1 charging rate of dnockout bottle as 12.1g/min, sets the charging of dnockout bottle 2
Speed is 2.85g/min, sets the charging rate of dnockout bottle 3 as 0.47g/min.Conversion zone retention time 1h, continuous coil pipe are anti-
Answer the control of device internal pressure in 1.0~2.0MPa.The system of reaction is passed directly into hydrogen chloride/methanol solution, carries out in 0~10 DEG C of temperature control
It is quenched.Methanol is concentrated under reduced pressure out in system after the completion of being quenched, and residue obtains net product white by cooling after vacuum distillation
The total 52.2g of solid, purity 98.5%, yield 61.2%.
Above-mentioned white solid product is detected by nuclear-magnetism and high resolution mass spectrum, and testing result is as follows:
1H NMR(500MHz,CDCl3) δ: 7.52 (d, J=5.0Hz, 1H), 6.72 (d, J=5.0Hz, 1H), 5.07 (m,
1H),4.93(m,1H),4.88(s,2H),1.87(s,3H).
HRMS(ESI)m/z[M+H]+Calcd for C9H10O3S 198.2389,found 198.2364.
It can be seen from the above description that the above embodiments of the present invention realized the following chievements:
The application usesIt is raw material with E-3- methoxy-methyl acrylate, makes the two under alkaline condition
It carries out condensation reaction and forms thiphene ring, above-mentioned reaction is easy to carry out, easy control of reaction conditions, and product yield is higher.Above-mentioned E-
Cost is relatively low relative to 2- chloracrylic acid methyl esters or Methyl propiolate for 3- methoxy-methyl acrylate, therefore reduces 3- hydroxyl
The synthesis technology cost of base thiophene-2-carboxylic acid ester type compound.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of 3- hydroxy thiophene -2- carboxylic acid ester compound characterized by comprising
MakeIt carries out condensation reaction under alkaline condition with E-3- methoxy-methyl acrylate and forms 3- hydroxyl thiophene
Pheno -2- carboxylic acid ester compound, wherein any one in the alkenyl of alkyl of the R selected from C1~C10, C2~C10.
2. preparation method according to claim 1, which is characterized in that the R is selected from-CH3、-C2H5、-C3H8、-C4H10、-
C5H12、-C6H14、-C7H16、-C8H18、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH(CH3)(C2H5)、-CH2CH=
CH2、 In any one.
3. preparation method according to claim 1, which is characterized in that the preparation method includes:
It willIt is mixed with the first solvent, forms the first material liquid；
E-3- methoxy-methyl acrylate is mixed with the second solvent, forms the second material liquid；
First material liquid, the second material liquid and alkaline conditioner are continuously passed through in continuous reaction device and carry out serialization
Condensation reaction forms the 3- hydroxy thiophene -2- carboxylic acid ester compound.
4. preparation method according to claim 3, which is characterized in that first solvent and second solvent are respectively only
On the spot just selected from water, methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, chloroform, methylene chloride, ethyl acetate, triethylamine, three
Propylamine, diisopropyl ethyl amine, tetrahydrofuran, 2- methyltetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, diethyl two
Diethylene glycol dimethyl ether, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- diethylformamide, N-
Methyl pyrrolidone, dimethyl sulfoxide and acetonitrile composition group in any one or more.
5. preparation method according to claim 3, which is characterized in that the alkaline conditioner be selected from sodium methoxide, potassium methoxide,
Sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, Tri-n-Propylamine, diisopropyl ethyl amine, tert-butylamine, triethylene
Diamines, diazabicylo, KOH, NaOH, K2CO3、Na2CO3、NaHCO3、Cs2CO3、KHCO3, sodium acetate composition group in it is any
It is one or more.
6. preparation method according to claim 3, which is characterized in that describedWith the E-3- methoxyl group
The molar ratio of methyl acrylate is 1:1~3:1, preferably 1.5:1~2.5:1, the E-3- methoxy-methyl acrylate and institute
The molar ratio for stating alkaline conditioner is 1:5~1:1, preferably 1:3.5~1:2.5.
7. preparation method according to claim 3, which is characterized in that the serialization condensation reaction at 0~200 DEG C into
Row, preferably carries out at 50~150 DEG C.
8. preparation method according to claim 3, which is characterized in that pressure of the serialization condensation reaction in 1~2MPa
Strong lower progress, the retention time of the preferably described serialization condensation reaction are 30~120min.
9. preparation method according to claim 3, which is characterized in that the preparation method further include:
It is quenched, is obtained at 0~10 DEG C using the system that hydrogen chloride/methanol solution obtains the serialization condensation reaction
System is quenched；
The system that is quenched is purified, the 3- hydroxy thiophene -2- carboxylic acid ester compound is obtained.
10. preparation method according to claim 9, which is characterized in that the purification includes:
It carries out the system that is quenched to be concentrated under reduced pressure to give residue and methanol；
The residue is evaporated under reduced pressure, the 3- hydroxy thiophene -2- carboxylic acid ester compound is obtained.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575286A (en) * | 2001-10-25 | 2005-02-02 | 伊莱利利公司 | Thiophene-amd thiazolesulfonamides as antineoplastic agents |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1575286A (en) * | 2001-10-25 | 2005-02-02 | 伊莱利利公司 | Thiophene-amd thiazolesulfonamides as antineoplastic agents |
Non-Patent Citations (1)
| Title |
|---|
| KARP, GARY M.等: "《Preparation of 4-Hydroxy-2-trifluoromethylthiophene: A Novel Bioisostere of α,α,α-Trifluoro-m-cresol》", 《SYNTHESIS》 * |
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