CN107011301B - A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method - Google Patents
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method Download PDFInfo
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- CN107011301B CN107011301B CN201710388412.0A CN201710388412A CN107011301B CN 107011301 B CN107011301 B CN 107011301B CN 201710388412 A CN201710388412 A CN 201710388412A CN 107011301 B CN107011301 B CN 107011301B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention discloses a kind of 2-(2- methoxyphenyls) high-efficiency synthesis method of -5- oxo-tetrahydrofuran -3- carboxylic acid, using o-methoxybenzaldehyde, succinic anhydride as raw material, use caddy/triethylamine for catalyst, 2-(2- methoxyphenyl is obtained by reaction in aprotic atent solvent) -5- oxo-tetrahydrofuran -3- carboxylic acid, synthesis technology reaction raw materials of the invention are cheap and easy to get, reaction process is simply easy to control, product post-processing step is few, high income, product purity is high, it is at low cost, adapt to large-scale industrial production.Preparation method of the invention overcome use in the prior art zinc chloride as catalyst when must high temperature remove water to obtain higher yields the shortcomings that, caddy does not need high-temperature roasting water removal, is not in turn the difficult situation of material, is suitable for industrialized production.
Description
Technical field
The present invention relates to the synthetic method technical field of tetrahydrofuran derivatives, specifically a kind of 2-(2- methoxybenzene
Base) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method.
Background technique
2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid is commonly called as 2- methoxyl group paraconic acid, and No. CAS:
117621-06-4.It is the 3- carboxylic acid -5- oxo-tetrahydrofuran derivative that aryl replaces, and is mainly used for medicine, pesticide intermediate
Synthesis, be the key intermediate of antidiabetic object Mitiglinide II.
Patent WO2008089461 disclose it is a kind of for diabetes, cancer, inflammation, nerve decline illness, infection and
The synthesis of the cyclohexadione compounds of cardiovascular disease and application method.- 3- the carboxylic acid-wherein replaced comprising related intermediate aryl
The synthesis and separation process of 5- oxo-tetrahydrofuran.Wherein o-methoxybenzaldehyde and succinic anhydride are in zinc chloride/tri-
The lower room temperature reaction of ethamine catalysis for 24 hours, obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid, yield only has 49%.
Patent WO2005040109 discloses a kind of for treating the black cortical hormone receptor chemical combination of casting skin matter hormone disturbance
The structure and application method of object.It is directed to the paraconic acid synthetic method of step important intermediate aryl substitution.In toluene solvant
In, using anhydrous sodium acetate as catalyst, 4- chlorobenzaldehyde and succinic anhydride back flow reaction obtain 2-(4- chlorphenyl) -5- oxo four
Hydrogen furans -3- carboxylic acid, yield 33%.
The Joe A. Tran(Bioorganic &Medicinal of American Psychiatry endocrine bioscience research institute
Chemistry Letters 18(2008) 1124-1130) et al. have studied thiophane as black -4 receptor of cortin
With the synthetic method of tetrahydrofuran derivatives.It wherein also contains p-chlorobenzaldehyde and prepares corresponding paraconic acid to succinic anhydride reaction
The step of, synthetic technology method is consistent with patent WO2005040109.
Haveing the defects that for above-mentioned synthetic method is important: 1, reaction yield is low, and highest only has 49%, and treatment process is cumbersome, closes
At at high cost.2, experimenter has found during the experiment, and zinc chloride hygroscopicity is strong, is not easy dry water removal, preferable to obtain
Yield, zinc chloride needs high-temperature roasting to remove water, and the requirement to reaction environment is high, and it is difficult to turn material, is not suitable for industrialized production.
Summary of the invention
To solve the above problems, the object of the present invention is to provide a kind of 2-(2- methoxyphenyls) -5- oxo-tetrahydrofuran -
The preparation method of 3- carboxylic acid.
The present invention to achieve the above object, is achieved through the following technical solutions:
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent, caddy is then added thereto, obtains
The temperature of mixed liquor is reduced to 0 ~ 5 DEG C, and triethylamine is added dropwise thereto at such a temperature by mixed liquor, is added dropwise and is warming up to
It 20 ~ 140 DEG C of reaction temperature, reacts 6 ~ 48 hours, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent, caddy and triethylamine molal volume ratio be
0.1mol:0.1 ~ 0.2mol:100 ~ 150ml:0.2 ~ 0.25mol:0.2 ~ 0.25mol；
The aprotic solvent is methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, toluene or dimethylbenzene；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2 ~ 3, liquid separation, organic phase unsaturated carbonate
The washing of hydrogen sodium solution, merges water phase, will merge water phase salt acid for adjusting pH to 2 ~ 3, and yellow solid is precipitated, and filtering obtains filter cake；It will
Gained filter cake re crystallization from toluene, obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid；1. gained is anti-for step
The volume ratio for answering liquid, water and toluene is 1:0.8 ~ 1:0.5 ~ 1.
Preferably, aprotic solvent is methylene chloride or dimethylbenzene.
Preferably, the molal volume ratio of o-methoxybenzaldehyde, succinic anhydride, dimethylbenzene, caddy and triethylamine is
0.1mol:0.15mol:120ml:0.2mol:0.2mol.
Preferably, reaction temperature is 20 ~ 50 DEG C.
Preferably, step 1. gained reaction solution, water and toluene volume ratio be 1:1:0.5.
Further preferred preparation method, comprising the following steps:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent dimethylbenzene, chlorination is then added thereto
Cadmium obtains mixed liquor, the temperature of mixed liquor is reduced to 0 DEG C, and triethylamine is added dropwise thereto at such a temperature, liter is added dropwise
Temperature reacts 15 hours to 50 DEG C of reaction temperature, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent dimethylbenzene, caddy and triethylamine molal volume ratio be
0.1mol:0.15mol:120ml:0.2mol:0.2mol；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2, liquid separation, organic phase unsaturated carbonate hydrogen
Sodium solution washing, merges water phase, will merge water phase salt acid for adjusting pH to 2, and yellow solid is precipitated, and filtering obtains filter cake；By gained
Filter cake re crystallization from toluene obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid；Step 1. gained reaction solution,
The volume ratio of water and toluene is 1:1:0.5.
The present invention has the advantage that compared with prior art
The present invention provides 2-(2- methoxyphenyls) the new technique road of the synthesis of -5- oxo-tetrahydrofuran -3- carboxylic acid
Line, using o-methoxybenzaldehyde and succinic anhydride as raw material, using caddy/triethylamine as catalyst, reaction raw materials are cheap and easy to get,
Reaction process is simply easy to control, and product post-processing step is few, high income, and product purity is high, at low cost, adapts to large-scale industry
Metaplasia produces.
Preparation method of the invention overcome in the prior art using zinc chloride as catalyst when must high temperature remove water
The shortcomings that obtain higher yields, caddy do not need high-temperature roasting water removal, are not in turn the difficult situation of material, are suitable for industry
Metaplasia produces.
Specific embodiment
The object of the present invention is to provide a kind of 2-(2- methoxyphenyls) the preparation side of -5- oxo-tetrahydrofuran -3- carboxylic acid
Method is achieved through the following technical solutions:
Synthetic method of the invention, using o-methoxybenzaldehyde, succinic anhydride as raw material, use caddy/triethylamine for
Catalyst obtains target product, reaction route by single step reaction are as follows:
。
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent, caddy is then added thereto, obtains
The temperature of mixed liquor is reduced to 0 ~ 5 DEG C, and triethylamine is added dropwise thereto at such a temperature by mixed liquor, is added dropwise and is warming up to
It 20 ~ 140 DEG C of reaction temperature, reacts 6 ~ 48 hours, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent, caddy and triethylamine molal volume ratio be
0.1mol:0.1 ~ 0.2mol:100 ~ 150ml:0.2 ~ 0.25mol:0.2 ~ 0.25mol；
The aprotic solvent is methylene chloride, chloroform, carbon tetrachloride, dichloroethanes, toluene or dimethylbenzene；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2 ~ 3, liquid separation, organic phase unsaturated carbonate
The washing of hydrogen sodium solution, merges water phase, will merge water phase salt acid for adjusting pH to 2 ~ 3, and yellow solid is precipitated, and filtering obtains filter cake；It will
Gained filter cake re crystallization from toluene, obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid；1. gained is anti-for step
The volume ratio for answering liquid, water and toluene is 1:0.8 ~ 1:0.5 ~ 1.
Preferably, aprotic solvent is methylene chloride or dimethylbenzene.
Preferably, the molal volume ratio of o-methoxybenzaldehyde, succinic anhydride, dimethylbenzene, caddy and triethylamine is
0.1mol:0.15mol:120ml:0.2mol:0.2mol.
Preferably, reaction temperature is 20 ~ 50 DEG C.
Preferably, step 1. gained reaction solution, water and toluene volume ratio be 1:1:0.5.
Further preferred preparation method, comprising the following steps:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent dimethylbenzene, chlorination is then added thereto
Cadmium obtains mixed liquor, the temperature of mixed liquor is reduced to 0 DEG C, and triethylamine is added dropwise thereto at such a temperature, liter is added dropwise
Temperature reacts 15 hours to 50 DEG C of reaction temperature, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent dimethylbenzene, caddy and triethylamine molal volume ratio be
0.1mol:0.15mol:120ml:0.2mol:0.2mol；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2, liquid separation, organic phase unsaturated carbonate hydrogen
Sodium solution washing, merges water phase, will merge water phase salt acid for adjusting pH to 2, and yellow solid is precipitated, and filtering obtains filter cake；By gained
Filter cake re crystallization from toluene obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid；Step 1. gained reaction solution,
The volume ratio of water and toluene is 1:1:0.5.
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. 13.6g o-methoxybenzaldehyde, 10g succinic anhydride are dissolved in 100ml methylene chloride, then it is added thereto
36.6g caddy, obtains mixed liquor, and the temperature of mixed liquor is reduced to 0 DEG C, and 20.2g tri- is added dropwise thereto at such a temperature
Ethamine is added dropwise and is warming up to 20 DEG C of reaction temperature, reacts 48 hours, obtains reaction solution；
2. the water of 0.8 times of reaction solution volume is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2, liquid separation has
Machine is mutually washed with saturated sodium bicarbonate solution, merges water phase, will merge water phase salt acid for adjusting pH to 2, yellow solid, mistake is precipitated
Filter, obtains filter cake；By the gained filter cake re crystallization from toluene of 0.5 times of reaction solution volume, 21.54g 2-(2- methoxybenzene is obtained
Base) -5- oxo-tetrahydrofuran -3- carboxylic acid, product is faint yellow solid, and yield 91.2% is 98.6% with HPLC detection purity.
Embodiment 2
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. 13.6g o-methoxybenzaldehyde, 20g succinic anhydride are dissolved in 150ml chloroform, then it is added thereto
45.75g caddy, obtains mixed liquor, the temperature of mixed liquor is reduced to 5 DEG C, and 25.25g is added dropwise thereto at such a temperature
Triethylamine is added dropwise and is warming up to 140 DEG C of reaction temperature, reacts 6 hours, obtains reaction solution；
2. isometric water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 3, liquid separation, organic phase is used full
It is washed with sodium bicarbonate solution, merges water phase, water phase salt acid for adjusting pH to 3 will be merged, yellow solid is precipitated, filtering must filter
Cake；By gained filter cake use and the isometric re crystallization from toluene of water, obtain 21.68g 2-(2- methoxyphenyl) -5- oxo tetrahydro
Furans -3- carboxylic acid, product are faint yellow solid, and yield 91.8% is 99.0% with HPLC detection purity.
Embodiment 3
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. 13.6g o-methoxybenzaldehyde, 12g succinic anhydride are dissolved in 140ml carbon tetrachloride, then it is added thereto
43.92g caddy, obtains mixed liquor, the temperature of mixed liquor is reduced to 4 DEG C, and 22.22g is added dropwise thereto at such a temperature
Triethylamine is added dropwise and is warming up to 100 DEG C of reaction temperature, reacts 20 hours, obtains reaction solution；
2. the water of 0.9 times of reaction solution volume is added into step 1. gained reaction solution, with salt acid for adjusting pH to 3, liquid separation has
Machine is mutually washed with saturated sodium bicarbonate solution, merges water phase, will merge water phase salt acid for adjusting pH to 3, yellow solid, mistake is precipitated
Filter, obtains filter cake；By the gained filter cake re crystallization from toluene of 0.6 times of reaction solution volume, 21.83g 2-(2- methoxybenzene is obtained
Base) -5- oxo-tetrahydrofuran -3- carboxylic acid, product is faint yellow solid, and yield 92.4% is 99.0% with HPLC detection purity.
Embodiment 4
A kind of 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid preparation method, comprising the following steps:
1. 13.6g o-methoxybenzaldehyde, 15g succinic anhydride are dissolved in 120ml dimethylbenzene, then it is added thereto
36.6g caddy, obtains mixed liquor, and the temperature of mixed liquor is reduced to 0 DEG C, and 20.2g tri- is added dropwise thereto at such a temperature
Ethamine is added dropwise and is warming up to 50 DEG C of reaction temperature, reacts 15 hours, obtains reaction solution；
2. isometric water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2, liquid separation, organic phase is used full
It is washed with sodium bicarbonate solution, merges water phase, water phase salt acid for adjusting pH to 2 will be merged, yellow solid is precipitated, filtering must filter
Cake；By the gained filter cake re crystallization from toluene of 0.5 times of reaction solution volume, 22.16g2-(2- methoxyphenyl is obtained) -5- oxo
Tetrahydrofuran -3- carboxylic acid, product are faint yellow solid, and yield 93.8% is 99.5% with HPLC detection purity.
Comparative example 1
13.6g(0.1mol is put into 1L four-hole boiling flask) o-methoxybenzaldehyde, 30.4g(0.3mol) succinic anhydride,
40.8g(0.4mol is added dropwise at 0 DEG C in 61.6g(0.44mol) anhydrous zinc chloride (commercially available) and 360g methylene chloride) triethylamine, it protects
Hold 0-5 DEG C of dropping temperature.It is heated to back flow reaction after dripping off for 24 hours, pours into 250mL water, is acidified to pH=3 with concentrated hydrochloric acid.Liquid separation,
Water layer is extracted with dichloromethane twice, merges oil reservoir, with 100mL water washing.Obtained dichloromethane layer uses unsaturated carbonate hydrogen again
Sodium solution washs 3 times.Water layer is added dropwise concentrated hydrochloric acid and is acidified to pH=3, and solid is precipitated.200g methylene chloride is added, stirring and dissolving is divided
Liquid.Oil reservoir removed under reduced pressure solvent, residue 80g re crystallization from toluene obtain faint yellow solid product 7.0g, and content 81.4% is received
Rate 29%.
Comparative example 2
13.6g(0.1mol is put into 1L four-hole boiling flask) o-methoxybenzaldehyde, 25.3g(0.25mol) succinic anhydride,
61.6g(0.44mol) anhydrous zinc chloride (handles) and 360g methylene chloride by high-temperature roasting, 20.4g is added dropwise at 0 DEG C
(0.2mol) triethylamine is kept for 0-5 DEG C of dropping temperature.It is heated to 44 DEG C of back flow reactions after dripping off for 24 hours, pours into 250mL water, use is dense
Hydrochloric acid is acidified to pH=2.Liquid separation, water layer are extracted with dichloromethane twice, merge oil reservoir, with 100mL water washing.Obtained dichloro
Methane layer is washed 3 times with saturated sodium bicarbonate solution again.Water layer is added dropwise concentrated hydrochloric acid and is acidified to pH=2, and solid is precipitated.200g is added
Methylene chloride, stirring and dissolving, liquid separation.Oil reservoir removed under reduced pressure solvent, residue 80g re crystallization from toluene, obtains faint yellow solid
Product 15.8g, content 80.6%, yield 66.7%.
Claims (5)
1. a kind of 2-(2- methoxyphenyl) preparation method of -5- oxo-tetrahydrofuran -3- carboxylic acid, it is characterised in that: including with
Lower step:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent, caddy is then added thereto, is mixed
The temperature of mixed liquor is reduced to 0 ~ 5 DEG C, and triethylamine is added dropwise thereto at such a temperature by liquid, is added dropwise and is warming up to reaction
Temperature is 20 ~ 50 DEG C, reacts 6 ~ 48 hours, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent, caddy and triethylamine molal volume ratio be 0.1mol:0.1
~ 0.2mol:100 ~ 150ml:0.2 ~ 0.25mol:0.2 ~ 0.25mol；
The aprotic solvent is methylene chloride or dimethylbenzene；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2 ~ 3, liquid separation, organic phase saturated sodium bicarbonate
Solution washing, merges water phase, will merge water phase salt acid for adjusting pH to 2 ~ 3, and yellow solid is precipitated, and filtering obtains filter cake；By gained
Filter cake re crystallization from toluene obtains 2-(2- methoxyphenyl) -5- oxo-tetrahydrofuran -3- carboxylic acid；
Step 1. gained reaction solution, water and toluene volume ratio be 1:0.8 ~ 1:0.5 ~ 1.
2. 2-(2- methoxyphenyl according to claim 1) preparation method of -5- oxo-tetrahydrofuran -3- carboxylic acid,
Be characterized in that: o-methoxybenzaldehyde, succinic anhydride, dimethylbenzene, caddy and triethylamine molal volume ratio be 0.1mol:
0.15mol:120ml:0.2mol:0.2mol.
3. 2-(2- methoxyphenyl according to claim 1) preparation method of -5- oxo-tetrahydrofuran -3- carboxylic acid,
Be characterized in that: the reaction time is 12 ~ 15 hours.
4. 2-(2- methoxyphenyl according to claim 1) preparation method of -5- oxo-tetrahydrofuran -3- carboxylic acid,
Be characterized in that: step 1. gained reaction solution, water and toluene volume ratio be 1:1:0.5.
5. 2-(2- methoxyphenyl according to claim 1) preparation method of -5- oxo-tetrahydrofuran -3- carboxylic acid,
It is characterized in that: the following steps are included:
1. o-methoxybenzaldehyde, succinic anhydride are dissolved in aprotic solvent dimethylbenzene, caddy is then added thereto, obtains
To mixed liquor, the temperature of mixed liquor is reduced to 0 DEG C, and triethylamine is added dropwise thereto at such a temperature, is added dropwise and is warming up to
It 50 DEG C of reaction temperature, reacts 15 hours, obtains reaction solution；
O-methoxybenzaldehyde, succinic anhydride, aprotic solvent dimethylbenzene, caddy and triethylamine molal volume ratio be
0.1mol:0.15mol:120ml:0.2mol:0.2mol；
2. water is added into step 1. gained reaction solution, with salt acid for adjusting pH to 2, liquid separation, organic phase saturated sodium bicarbonate is molten
Liquid washing, merges water phase, will merge water phase salt acid for adjusting pH to 2, and yellow solid is precipitated, and filtering obtains filter cake；By gained filter cake
With re crystallization from toluene, 2-(2- methoxyphenyl is obtained) -5- oxo-tetrahydrofuran -3- carboxylic acid；
Step 1. gained reaction solution, water and toluene volume ratio be 1:1:0.5.
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