CN105254611B - The preparation method of the carboxylic acid of benzothiophene 2 - Google Patents
The preparation method of the carboxylic acid of benzothiophene 2 Download PDFInfo
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- CN105254611B CN105254611B CN201510758158.XA CN201510758158A CN105254611B CN 105254611 B CN105254611 B CN 105254611B CN 201510758158 A CN201510758158 A CN 201510758158A CN 105254611 B CN105254611 B CN 105254611B
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- benzothiophene
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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
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of preparation method of the carboxylic acid of benzothiophene 2, in high-pressure bottle, using 3 sulfydryl cumarins as raw material, reacted using TBAB as catalyst in alkali lye；First the pressure in regulation high-pressure bottle is 0.8~1.2Mpa, is then heated to 130~160 DEG C of 7~10h of reaction；Catalyst is 2~12.5mol% of raw material, and alkali is 1.5~3.6 moles times of raw material；Reaction end is cooled to addition concentrated hydrochloric acid after room temperature and is acidified to reaction product pH=3~4, and filtration drying obtains the carboxylic acid of benzothiophene 2.
Description
Technical field
The present invention relates to a kind of synthetic method of organic compound, particularly a kind of synthesis side of benzothiophene -2- carboxylic acids
Method.
Background technology
Benzothiophene -2- carboxylic acids and its derivative are widely used in the fields such as medicine, agricultural chemicals, are also synthesis benzothiophene
Important intermediate, its structural formula is as shown in S-1.
The synthetic method for having the benzothiophene -2- carboxylic acids of document report at present has following several：
(1) using o-chlorobenzaldehyde, methyl mercaptan and monoxone as raw material
Kagano et al. (US 9258630) is using o-chlorobenzaldehyde and methyl mercaptan as raw material, in alkalescence and phase transfer catalyst
Reaction obtains 2- methylthio phenyl formaldehyde under conditions of (TBAB, TBAB) is present, and yield is up to 95%；2- methylthio phenyl first
Aldehyde and chloroacetate reaction generate benzothiophene -2- carboxylic acids, and yield is up to 80%.The raw materials used monoxone of this method is toxic articles, and
Methyl mercaptan easily reacts with water and monoxone in course of reaction can produce poisonous and inflammable gas.Reaction equation is as follows：
(2) using the alkali metal salt of o-chlorobenzaldehyde and TGA as raw material
Kokai et al. (JP 05194484) is using the alkali metal salt of o-chlorobenzaldehyde and TGA as raw material, first condensation life
Into intermediate 2- Fonnylphenyl thiacetates, intermediate is cyclized generation benzothiophene -2- carboxylates in the basic conditions, acid
Benzothiophene -2- carboxylic acids are obtained after change.This method need to carry out in anhydrous conditions and needed in course of reaction 2 kinds be used for separate
Organic solvent.Reaction equation is as follows：
In formula：R is alkali metal.
(3) using o-chlorobenzaldehyde and TGA as raw material
Brouwer et al. (WO 9947510) is urged using o-chlorobenzaldehyde, TGA potassium hydroxide as raw material in phase transfer
Under conditions of agent (TBAB, TBAB) is present, reaction obtains benzothiophene -2- carboxylic acids, and yield is up to more than 87.6%.
The course of reaction can consume substantial amounts of alkali and produce substantial amounts of waste water.Reaction equation is as follows：
The content of the invention
The technical problem to be solved in the present invention is to provide one kind using 3- sulfydryls cumarin be raw material in alkali and phase transfer catalysis (PTC)
Agent synthesizes benzothiophene -2- carboxylic acids method under conditions of existing.
In order to solve the above-mentioned technical problem, the present invention provides a kind of preparation method of benzothiophene -2- carboxylic acids, in high pressure-volume
In device (being, for example, autoclave), using 3- sulfydryls cumarin as raw material, carried out instead in alkali lye by catalyst of TBAB
Should；First the pressure in regulation high-pressure bottle is 0.8~1.2Mpa (being, for example, 1Mpa), is then heated to 130~160 DEG C of reactions 7
~10h；Catalyst is 2~12.5mol% of raw material, and alkali is 1.5~3.6 moles times of raw material；
Reaction end is cooled to addition concentrated hydrochloric acid after room temperature and is acidified to reaction product (i.e. kettle liquid) pH=3~4 (that is, in weak
It is acid), filtration drying obtains benzothiophene -2- carboxylic acids (being yellow solid).
It is used as the improvement of the preparation method of the benzothiophene -2- carboxylic acids of the present invention：The mass concentration of alkali is 20% in alkali lye
~40%.
It is used as the further improvement of the preparation method of the benzothiophene -2- carboxylic acids of the present invention：Alkali is sodium hydroxide, hydroxide
Magnesium, potassium hydroxide, calcium hydroxide.
In the present invention, concentrated hydrochloric acid refers to 36.5wt% HCl solution.
The reaction equation of the benzothiophene -2- carboxylic acids synthesis of the present invention is as follows：
The invention provides the synthetic method that benzothiophene -2- carboxylic acids are prepared by raw material of 3- sulfydryls cumarin, belong to complete
New process.The yield of the present invention is up to more than 40%.
Benzothiophene -2- carboxylic acids are prepared using the method for the present invention, with following technical advantage：3- sulfydryl cumarins be by
O-chlorobenzaldehyde and TGA prepare the accessory substance produced during benzothiophene -2- carboxylic acids, of the invention by accessory substance 3- mercaptos
Butylcoumariii is converted into benzothiophene -2- carboxylic acids, reduces the post processing cost of accessory substance 3- sulfydryl cumarins, generates simultaneously
The relatively broad product benzothiophene -2- carboxylic acids of purposes；Therefore, the present invention, which has, makes full use of waste, is produced into so as to reduce
This advantage.
Embodiment
The preparation method of embodiment 1, benzothiophene -2- carboxylic acids：
It is 30% that 17.8g (0.1mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.21mol (about 40g), 1.0g (0.003mol) TBAB, be filled with 1Mpa or so N2Afterwards
And it is heated to 135 DEG C of reaction 9h.Reaction end is cooled to room temperature addition concentrated hydrochloric acid (36.5wt%) to kettle liquid and (adjusted in faintly acid
Save pH=3-4), filtration cakes torrefaction (is dried to constant weight), obtains yellow solid 8.8g, be benzothiophene -2- by filtering in 100 DEG C
Carboxylic acid, yield is 49.4%.
The preparation method of embodiment 2, benzothiophene -2- carboxylic acids：
It is 25% that 35.6g (0.2mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.3mol (about 67g), 3.2g (0.010mol) TBAB, be filled with 1Mpa or so N2Afterwards simultaneously
It is heated to 135 DEG C of reaction 9h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 14.7g, is benzothiophene -2- carboxylic acids, yield is 41.3%.
The preparation method of embodiment 3, benzothiophene -2- carboxylic acids：
It is 40% that 71.3g (0.4mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 1.2mol (about 168g), 12.9g (0.050mol) TBAB, be filled with 1Mpa or so N2Afterwards
And it is heated to 130 DEG C of reaction 7h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 29.1g, is benzothiophene -2- carboxylic acids, yield is 40.8%.
The preparation method of embodiment 4, benzothiophene -2- carboxylic acids：
It is 20% that 14.3g (0.08mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.16mol (about 45g), 1.3g (0.004mol) TBAB, be filled with 1Mpa or so N2Afterwards
And it is heated to 160 DEG C of reaction 8h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 6.3g, is benzothiophene -2- carboxylic acids, yield is 44.1%.
The preparation method of embodiment 5, benzothiophene -2- carboxylic acids：
It is 30% that 16.0g (0.09mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.225mol (about 42g), 1.3g (0.004mol) TBAB, be filled with 1Mpa or so N2Afterwards
And it is heated to 145 DEG C of reaction 8h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 6.8g, is benzothiophene -2- carboxylic acids, yield is 42.5%.
The preparation method of embodiment 6, benzothiophene -2- carboxylic acids：
It is 35% that 35.6g (0.2mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.6mol (about 96g), 1.3g (0.004mol) TBAB, be filled with 1Mpa or so N2Afterwards simultaneously
It is heated to 130 DEG C of reaction 10h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 14.8g, is benzothiophene -2- carboxylic acids, yield is 41.6%.
The preparation method of embodiment 7, benzothiophene -2- carboxylic acids：
It is 30% that 17.8g (0.1mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.2mol (about 37g), 1g (0.003mol) TBAB, be filled with 1Mpa or so N2Afterwards and add
Heat reacts 10h to 135 DEG C.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, is filtered,
By filtration cakes torrefaction, yellow solid 7.4g is obtained, is benzothiophene -2- carboxylic acids, yield is 41.6%.
The preparation method of embodiment 8, benzothiophene -2- carboxylic acids：
It is 30% that 17.8g (0.1mol) 3- sulfydryls cumarin, mass fraction are added in the autoclave with stirring and temperature control
Potassium hydroxide aqueous solution 0.36mol (about 67g), 3.2g (0.01mol) TBAB, be filled with 1Mpa or so N2Afterwards simultaneously
It is heated to 140 DEG C of reaction 9h.Reaction is cooled to room temperature and adds concentrated hydrochloric acid (36.5wt%) to kettle liquid after terminating be in faintly acid, mistake
Filter, by filtration cakes torrefaction, obtains yellow solid 7.2g, is benzothiophene -2- carboxylic acids, yield is 40.4%.
The specific reaction condition and reaction result of each embodiment are summarized in table 1.
Table 1, the reaction condition of embodiment 1~8 and reaction result collect
Comparative example 1-1, by " mass fraction be 30% potassium hydroxide aqueous solution 0.21mol (about 40g) " in embodiment 1
Make into " mass fraction is 30% potassium hydroxide aqueous solution 0.42mol (about 80g) ", i.e. alkali is 4.2 moles times of raw material；Its
It is remaining to be equal to embodiment 1.Yield is 38.0%.
Comparative example 1-2, by " mass fraction be 30% potassium hydroxide aqueous solution 0.21mol (about 40g) " in embodiment 1
Make into " mass fraction is 30% potassium hydroxide aqueous solution 0.105mol (about 20g) ", i.e. alkali is 1.05 moles times of raw material；
Remaining is equal to embodiment 1.Yield is 35.2%.
Comparative example 2-1, by 30% make the concentration of potassium hydroxide aqueous solution in embodiment 1 into 50%, mole is constant, still
It is so 0.21mol, remaining is equal to embodiment 1.Yield is 38.7%.
Comparative example 2-2, by 30% make the concentration of potassium hydroxide aqueous solution in embodiment 1 into 10%, mole is constant, still
It is so 0.21mol, remaining is equal to embodiment 1.Yield is 26.8%.
Finally, in addition it is also necessary to it is noted that listed above is only several specific embodiments of the invention.Obviously, this hair
It is bright to be not limited to above example, there can also be many deformations.One of ordinary skill in the art can be from present disclosure
All deformations for directly exporting or associating, are considered as protection scope of the present invention.
Claims (1)
1. the preparation method of benzothiophene -2- carboxylic acids, it is characterised in that：In high-pressure bottle, using 3- sulfydryls cumarin as raw material,
Reacted using TBAB as catalyst in alkali lye；First the pressure in regulation high-pressure bottle is 0.8~1.2Mpa, so
After be heated to 130~160 DEG C reaction 7~10h；Catalyst is 2~12.5mol% of raw material, and alkali rubs for the 1.5~3.6 of raw material
You are again；
The mass concentration of alkali is 20%~40% in alkali lye, and alkali is sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide；
Reaction end, which is cooled to after room temperature, to be added concentrated hydrochloric acid and is acidified to reaction product pH=3~4, filtration drying obtain benzothiophene-
2- carboxylic acids.
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| CN106432015B (en) * | 2016-09-05 | 2018-01-26 | 江西仁明医药化工有限公司 | The method of overcritical chloromethanes synthesis THIOANISOLE |
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| US5965749A (en) * | 1998-03-16 | 1999-10-12 | Uniroyal Chemical Company, Inc. | Process for synthesizing substituted 2-benzo [b]thiophenecarboxylic acids and salts thereof |
| CN101775003B (en) * | 2010-02-04 | 2013-12-04 | 银杏树药业(苏州)有限公司 | Benzothiophene derivative, preparation method and application thereof |
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Address after: 332700 Jishan Industrial Park, Pengze, Jiujiang, Jiangxi Patentee after: Jiangxi Yang Fan New Material Co., Ltd. Address before: 332700 Jishan Industrial Park, Pengze, Jiujiang, Jiangxi Patentee before: Jiangxi Renming Pharmaceutical Chemical Industry Co., Ltd. |