CN106748725A - A kind of preparation method of the fluorobenzene propionic acid of 4 chlorine 2 - Google Patents
A kind of preparation method of the fluorobenzene propionic acid of 4 chlorine 2 Download PDFInfo
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- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The present invention relates to chemosynthesis technical field, a kind of especially preparation method of the fluorobenzene propionic acid of 4 chlorine 2, it is raw material by using the toluene fluoride of 4 chlorine 2 cheap and easy to get, by the total recovery of halo, nucleophilic displacement of fluorine, the fluorobenzene propionic acid of 4 chlorine of the prepared target product of hydrolysis decarboxylation three-step reaction 2, and target product up to 74%；And in processing procedure, its intermediate and final product can just be purified by the step such as extraction, reduction vaporization, suction filtration, recrystallization, and relative to cross for post purification process, its is simple to operate, easily realizes industrialized production.
Description
Technical field
The present invention relates to chemosynthesis technical field, the especially a kind of preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4-.
Background technology
The fluoro- benzenpropanoic acids of the chloro- 2- of 4- are important organic synthesis and medicine intermediates, are widely used in bactericide, ATX suppressions
The various aspects such as preparation, NHE3 inhibitor and nmda receptor antagonist.
Through retrieving consulting literatures, at present, the technological process of the fluoro- benzenpropanoic acid synthesis of 2- chloro- for 4- is mainly including following several
Kind：
(1) reports such as Musso, David L. with the chloro- 2- fluorophenols of 4- as raw material, with trifluoromethanesulfanhydride anhydride, acrylic acid
Ethyl ester obtains the target product 4- fluoro- benzenpropanoic acids of chloro- 2- by the reaction of 4 steps.
(2) Patent document number is the reports such as WO2010025856, WO2001092239 with the chloro- 2- fluoro cinnamic acids of 4- as former
Material, platinum dioxide or palladium are catalyst, by the hydrogen catalytic reduction reaction 4- fluoro- benzenpropanoic acids of chloro- 2-.
But, either the first above-mentioned synthetic route, or second above-mentioned synthetic route, its raw material for using
It is expensive, and the reaction time is more long, and production cost is higher, is especially required for platinum dioxide or palladium as catalyst so that
Prepared by product relatively costly；And the first synthetic route also needed to post purifying, the yield of the product for obtaining is relatively low, up to not
To 2%.
As can be seen here, the fluoro- benzenpropanoic acid complex synthetic routes of the chloro- 2- of 4- of the prior art, high cost, low yield, cost
It is high.
The content of the invention
In order to solve above-mentioned technical problem present in prior art, the present invention provides a kind of fluoro- benzenpropanoic acids of chloro- 2- of 4-
Preparation method.
It is achieved particular by following technical scheme：
The fluoro- benzenpropanoic acid synthetic routes of the chloro- 2- of 4- are as follows：
Wherein, R1It is Cl or Br；R2It is methyl and/or ethyl and/or benzyl；(1) it is halogenating reaction；(2) it is nucleophilic displacement of fluorine
Reaction；(3) for hydrolysis decarboxylation reacts.
The synthetic route is raw material by using the chloro- 2- toluene fluorides of 4- cheap and easy to get, by halo, nucleophilic displacement of fluorine, water
Solution decarboxylation three-step reaction is obtained the target product 4- fluoro- benzenpropanoic acids of chloro- 2-, and target product total recovery up to 74%；And
In processing procedure, its intermediate and final product just can be with by the step such as extraction, reduction vaporization, suction filtration, recrystallization
Purifying, relative to cross for post purification process, its is simple to operate, easily realizes industrialized production.
Specifically in above-mentioned synthetic route, using the step of, specifically include：
With the chloro- 2- toluene fluorides of 4- as raw material, compounds of formula I is obtained by halogenating reaction, compounds of formula I is through parent
Core substitution reaction obtains compounds of formula II, and compounds of formula II obtains the target product 4- fluoro- benzene of chloro- 2- through hydrolysis decarboxylation
Propionic acid；Formula I is：Wherein, R1It is Cl or Br；Formula II isWherein, R2It is methyl
And/or ethyl and/or benzyl.The effective synthetic route for shortening target product, reduces synthesis cost.
Specifically during halogenating reaction, the halide reagent that it is used is NCS or NBS；Halogenating agent and the chloro- 2- fluorine first of 4-
The molar ratio of benzene is 1~2:1.In the course of reaction, initiator and solvent treatment are added, wherein initiator is azo
Bis-isobutyronitrile；Solvent is carbon tetrachloride；Initiator is 0.01~0.02 with the molar ratio of the chloro- 2- toluene fluorides of 4-:1.Halo
The time of reaction is 6-12h.
In nucleophilic substitution, the nucleopilic reagent that it is used is diethyl malonate, dimethyl malenate or malonic acid
Dibenzyl ester；Nucleopilic reagent is 1~1.2 with the molar ratio of formula I:1；In the reaction, adding has alkali and solvent, and alkali is hydrogen
Change sodium, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or caustic alcohol；Solvent is tetrahydrofuran or DMF；Alkali and 4-
The molar ratio of chloro- 2- toluene fluorides is 1~2:1.The time of nucleophilic substitution is 2-5h.
Hydrolysis decarboxylation reaction in, the solvent that it is used for:Ethanol, methyl alcohol or isopropanol；Alkali is：NaOH, hydrogen-oxygen
Change the aqueous solution of potassium or lithium hydroxide；Acid is：Concentrated hydrochloric acid；It is specifically operated：During formula II is added into single port bottle, while
Add solvent and alkali so that its back flow reaction 2-4h；After completion of the reaction, decompression steam solvent, carry it is miscellaneous, collect water phase, add acid,
Back flow reaction 1.5-3h, reaction is finished, cooling, and extraction is dried, evaporated under reduced pressure solvent, recrystallization, you can.Above-mentioned alkali and original
The molar ratio ratio of material is：3~9:1；Acid is with the rate of charge of raw material：4~12:1.
The cost for synthesizing the 4- fluoro- benzenpropanoic acids of chloro- 2- by above method is relatively low, and yield is higher.
Specific embodiment
Technical scheme is further limited with reference to specific embodiment, but claimed
Scope is not only limited to description.
For " tetrahydrofuran solution of the chloro- 2- fluorobenzyl bromides (10.0g, 44.7mmol) of 4- being added dropwise in the examples below
(50mL) " refers to that the chloro- 2- fluorobenzyl bromides of 10g4- are dissolved in 50mL tetrahydrofurans, after the solution of formation, then is added dropwise.
Embodiment 1
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 500mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (20.0g, 138.3mmol) of 4-, NBS (24.6g,
138.3mmol), AIBN (0.3g, 2.1mmol) is dissolved in dry carbon tetrachloride (200mL), back flow reaction 8h.Reaction is finished,
Filtering, filter cake is washed with dichloromethane (60mL × 3), and filtrate adds water (250mL), dichloromethane (100mL × 3) extraction, anhydrous
Sodium sulphate is dried, and evaporated under reduced pressure solvent obtains the chloro- 2- fluorobenzyl bromides 28.2g of 4-, and yield is 91.2%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates
In 250mL there-necked flasks, diethyl malonate (7.2g, 44.7mmol) and dry tetrahydrofuran are added
(50ml), is cooled to 0 DEG C, adds sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection, stirs 20min, and 4- is added dropwise
The tetrahydrofuran solution (50mL) of chloro- 2- fluorobenzyl bromides (10.0g, 44.7mmol), completion of dropping is warmed to room temperature, and reacts 2.5h.Instead
Should finish, add water (30mL) be quenched reaction, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent
Obtain 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonate 12.2g, yield 90.4%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates (10.0g,
33.0mmol), the sodium hydrate aqueous solution (7.9g containing NaOH, 198.2mmol) of ethanol (30mL) and 2.5mol/L, backflow is anti-
Answer 4h.Reaction is finished, and removes ethanol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collection water phase, addition concentrated hydrochloric acid (9.6g containing HCl,
264.3mmol), back flow reaction 2h.Reaction is finished, and is cooled to room temperature, and ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate is done
Dry, evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 5.9g of the chloro- 2- of 4-, and yield is 88.3%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 2
A.4- the preparation of chloro- 2- fluorine benzyl chloride
In 250mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (10.0g, 69.2mmol) of 4-, NCS (9.2g, 69.2mmol),
AIBN (0.2g, 1.0mmol) is dissolved in dry carbon tetrachloride (120mL), back flow reaction 12h.Reaction is finished, filtering, filter cake
Washed with dichloromethane (30mL × 2), filtrate adds water (150mL), dichloromethane (60mL × 3) extraction, anhydrous sodium sulfate drying,
Evaporated under reduced pressure solvent obtains the chloro- 2- fluorine benzyl chloride 11.0g of 4-, and yield is 89.1%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates
In 250mL there-necked flasks, diethyl malonate (9.0g, 55.9mmol) and dry N, N- dimethyl formyl are added
Amine (50ml), is cooled to 0 DEG C, and potassium tert-butoxide (6.3g, 55.9mmol) is added in batches, stirs 20min, and the chloro- 2- fluorine of 4- is added dropwise
The DMF solution (50mL) of benzyl chloride (10.0g, 55.9mmol), completion of dropping is warmed to room temperature, and reacts 3.5h.
Reaction is finished, add water (30mL) be quenched reaction, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying, evaporated under reduced pressure is molten
Agent obtains 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonate 14.6g, yield 86.6%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates (10.0g,
33.0mmol), the sodium hydrate aqueous solution (7.9g containing NaOH, 198.2mmol) of methyl alcohol (30mL) and 2.5mol/L, backflow is anti-
Answer 3h.Reaction is finished, and removes methyl alcohol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collection water phase, addition concentrated hydrochloric acid (6.0g containing HCl,
165.2mmol), back flow reaction 3h.Reaction is finished, and is cooled to room temperature, and ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate is done
Dry, evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 5.8g of the chloro- 2- of 4-, and yield is 86.7%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 3
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 500mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (20.0g, 138.3mmol) of 4-, NBS (24.6g,
138.3mmol), AIBN (0.3g, 2.1mmol) is dissolved in dry carbon tetrachloride (200mL), back flow reaction 6h.Reaction is finished,
Filtering, filter cake is washed with dichloromethane (60mL × 3), and filtrate adds water (250mL), dichloromethane (100mL × 3) extraction, anhydrous
Sodium sulphate is dried, and evaporated under reduced pressure solvent obtains the chloro- 2- fluorine benzyl chloride 27.8g of 4-, and yield is 90.1%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates
In 250mL there-necked flasks, diethyl malonate (7.2g, 44.7mmol) and dry DMF (50ml), cooling are added
To 0 DEG C, addition sodium tert-butoxide (6.5g, 67.1mmol) in batches, the chloro- 2- fluorobenzyl bromides of stirring 20min, dropwise addition 4- (10.0g,
Tetrahydrofuran solution (50mL) 55.9mmol), completion of dropping is warmed to room temperature, and reacts 4h.Reaction is finished, add water (30mL) quench
Go out reaction, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent obtains 2- [(the chloro- 2- fluorine of 4-) benzyls
Base] -1,3- diethyl malonate 12.0g, yield 88.7%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates (10.0g,
33.0mmol), the potassium hydroxide aqueous solution (11.1g containing KOH, 198.2mmol) of isopropanol (30mL) and 2.5mol/L, backflow
Reaction 3h.Reaction is finished, and removes isopropanol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collects water phase, adds concentrated hydrochloric acid (to contain HCl
4.8g, 132.1mmol), back flow reaction 3h.Reaction is finished, and is cooled to room temperature, ethyl acetate (100mL × 3) extraction, anhydrous sulphur
Sour sodium is dried, and evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 5.7g of the chloro- 2- of 4-, and yield is 85.6%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 4
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 500mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (20.0g, 138.3mmol) of 4-, NBS (24.6g,
138.3mmol), AIBN (0.3g, 2.1mmol) is dissolved in dry carbon tetrachloride (200mL), back flow reaction 8h.Reaction is finished,
Filtering, filter cake is washed with dichloromethane (60mL × 3), and filtrate adds water (250mL), dichloromethane (100mL × 3) extraction, anhydrous
Sodium sulphate is dried, and evaporated under reduced pressure solvent obtains the chloro- 2- fluorobenzyl bromides 28.7g of 4-, and yield is 92.8%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- dimethyl malenates
In 250mL there-necked flasks, dimethyl malenate (5.9g, 44.7mmol) and dry tetrahydrofuran are added
(50ml), is cooled to 0 DEG C, and sodium methoxide (3.6g, 67.1mmol) is added in batches, stirs 20min, and the chloro- 2- fluorobenzyl bromides of 4- are added dropwise
The tetrahydrofuran solution (50mL) of (10.0g, 44.7mmol), completion of dropping is warmed to room temperature, and reacts 5h.Reaction is finished, and is added water
(30mL) is quenched reaction, and ethyl acetate (100mL × 3) is extracted, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 2-, and [(4- is chloro-
2- fluorine) benzyl] -1,3- dimethyl malenate 11.0g, yield 89.6%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- dimethyl malenates (10.0g,
36.4mmol), the lithium hydroxide aqueous solution (2.6g containing LiOH, 109.2mmol) of ethanol (30mL) and 2.5mol/L, backflow is anti-
Answer 4h.Reaction is finished, and removes ethanol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collection water phase, addition concentrated hydrochloric acid (10.6g containing HCl,
291.3mmol), back flow reaction 2h.Reaction is finished, and is cooled to room temperature, and ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate is done
Dry, evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 6.4g of the chloro- 2- of 4-, and yield is 87.4%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 5
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 500mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (20.0g, 138.3mmol) of 4-, NBS (36.9g,
207.5mmol), AIBN (0.2g, 1.4mmol) is dissolved in dry carbon tetrachloride (200mL), back flow reaction 7h.Reaction is finished,
Filtering, filter cake is washed with dichloromethane (60mL × 3), and filtrate adds water (250mL), dichloromethane (100mL × 3) extraction, anhydrous
Sodium sulphate is dried, and evaporated under reduced pressure solvent obtains the chloro- 2- fluorobenzyl bromides 25.2g of 4-, and yield is 81.5%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] Bian ester of -1,3- malonic acid two
In 250mL there-necked flasks, the Bian ester (15.3g, 53.7mmol) of malonic acid two and dry tetrahydrofuran are added
(50ml), is cooled to 0 DEG C, and caustic alcohol (6.1g, 89.5mmol) is added in batches, stirs 20min, and the chloro- 2- fluorobenzyl bromides of 4- are added dropwise
The tetrahydrofuran solution (50mL) of (10.0g, 44.7mmol), completion of dropping is warmed to room temperature, and reacts 5h.Reaction is finished, and is added water
(30mL) is quenched reaction, and ethyl acetate (100mL × 3) is extracted, anhydrous sodium sulfate drying, and evaporated under reduced pressure solvent obtains 2-, and [(4- is chloro-
2- fluorine) benzyl] the Bian ester 16.9g of -1,3- malonic acid two, yield 88.4%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] Bian ester of -1,3- malonic acid two (10.0g,
23.5mmol), the sodium hydrate aqueous solution (5.6g containing NaOH, 140.9mmol) of ethanol (30mL) and 2.5mol/L, backflow is anti-
Answer 3.5h.Reaction is finished, and removes ethanol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collects water phase, adds concentrated hydrochloric acid (to contain HCl
6.9g, 187.9mmol), back flow reaction 2h.Reaction is finished, and is cooled to room temperature, ethyl acetate (100mL × 3) extraction, anhydrous sulphur
Sour sodium is dried, and evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 4.2g of the chloro- 2- of 4-, and yield is 88.1%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 6
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 500mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (20.0g, 138.3mmol) of 4-, NBS (27.1g,
152.2mmol), AIBN (0.3g, 2.1mmol) is dissolved in dry carbon tetrachloride (200mL), back flow reaction 8h.Reaction is finished,
Filtering, filter cake is washed with dichloromethane (60mL × 3), and filtrate adds water (250mL), dichloromethane (100mL × 3) extraction, anhydrous
Sodium sulphate is dried, and evaporated under reduced pressure solvent obtains the chloro- 2- fluorobenzyl bromides 27.6g of 4-, and yield is 89.2%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates
In 250mL there-necked flasks, diethyl malonate (7.9g, 49.2mmol) and dry tetrahydrofuran are added
(50ml), is cooled to 0 DEG C, adds sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection, stirs 20min, and 4- is added dropwise
The tetrahydrofuran solution (50mL) of chloro- 2- fluorobenzyl bromides (10.0g, 44.7mmol), completion of dropping is warmed to room temperature, and reacts 2h.Reaction
Finish, add water (30mL) be quenched reaction, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent is obtained
2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonate 12.1g, yield 89.3%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates (10.0g,
33.0mmol), the potassium hydroxide aqueous solution (16.7g containing KOH, 297.3mmol) of methyl alcohol (30mL) and 2.5mol/L, backflow is anti-
Answer 2h.Reaction is finished, and removes methyl alcohol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collection water phase, addition concentrated hydrochloric acid (7.2g containing HCl,
198.2mmol), back flow reaction 2h.Reaction is finished, and is cooled to room temperature, and ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate is done
Dry, evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 5.8g of the chloro- 2- of 4-, and yield is 86.8%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
Embodiment 7
A.4- the preparation of chloro- 2- fluorobenzyl bromides
In 250mL eggplant-shape bottles, by the chloro- 2- toluene fluorides (10.0g, 69.2mmol) of 4-, NBS (12.3g, 69.2mmol),
AIBN (0.1g, 0.8mmol) is dissolved in dry carbon tetrachloride (120mL), back flow reaction 8h.Reaction is finished, and filtering, filter cake is used
Dichloromethane (30mL × 2) is washed, and filtrate adds water (150mL), and dichloromethane (60mL × 3) extraction, anhydrous sodium sulfate drying subtracts
Pressure solvent evaporated obtains the chloro- 2- fluorobenzyl bromides 14.3g of 4-, and yield is 92.4%.
B.2- the preparation of [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates
In 250mL there-necked flasks, diethyl malonate (7.9g, 49.2mmol) and dry tetrahydrofuran are added
(50ml), is cooled to 0 DEG C, adds sodium hydrogen (1.6g, 67.1mmol) in batches under nitrogen protection, stirs 20min, and 4- is added dropwise
The tetrahydrofuran solution (50mL) of chloro- 2- fluorobenzyl bromides (10.0g, 44.7mmol), completion of dropping is warmed to room temperature, and reacts 2.5h.Instead
Should finish, add water (30mL) be quenched reaction, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent
Obtain 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonate 12.3g, yield 90.9%.
C.4- the preparation of the fluoro- benzenpropanoic acids of chloro- 2-
In 250mL single port bottles, addition 2- [(the chloro- 2- fluorine of 4-) benzyl] -1,3- diethyl malonates (10.0g,
33.0mmol), the sodium hydrate aqueous solution (10.6g containing NaOH, 264.3mmol) of ethanol (30mL) and 2.5mol/L, backflow is anti-
Answer 3h.Reaction is finished, and removes ethanol under reduced pressure, and ether (50mL × 2) carries miscellaneous, collection water phase, addition concentrated hydrochloric acid (14.5g containing HCl,
396.4mmol), back flow reaction 1.5h.Reaction is finished, and is cooled to room temperature, ethyl acetate (100mL × 3) extraction, anhydrous sodium sulfate
Dry, evaporated under reduced pressure solvent, ethyl alcohol recrystallization twice, obtains final product the fluoro- benzenpropanoic acid 5.9g of the chloro- 2- of 4-, and yield is 88.7%.
1H-NMR(CDCl3):2.650-2.688(t,2H,)；2.924-2.961(t,2H)；7.043-7.076(q,2H)；
7.135-7.176(t,1H)。
The invention is raw material by using the chloro- 2- toluene fluorides of 4- cheap and easy to get, by halo, nucleophilic displacement of fluorine, water
Solution decarboxylation three-step reaction is obtained the target product 4- fluoro- benzenpropanoic acids of chloro- 2-, and total recovery is up to 74%, and above-described embodiment is only limitted to
The technical scheme of the invention is made explanations and illustrated, is not the further limit to the technical scheme of the invention
Fixed, the improvement of the essential characteristics and non-significant progress of the non-protruding that those skilled in the art make on this basis is belonged to
The protection domain of the invention.
Claims (8)
1. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of a kind of 4-, it is characterised in that synthetic route is as follows：
Wherein, R1It is Cl or Br；R2It is methyl and/or ethyl and/or benzyl；(1) it is halogenating reaction；(2) for nucleophilic displacement of fluorine is anti-
Should；(3) for hydrolysis decarboxylation reacts.
2. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1, it is characterised in that specific preparation process be with
The chloro- 2- toluene fluorides of 4- are raw material, and compounds of formula I, compounds of formula I nucleo philic substitution reaction are obtained by halogenating reaction
Compounds of formula II is obtained, compounds of formula II obtains the target product 4- fluoro- benzenpropanoic acids of chloro- 2- through hydrolysis decarboxylation；Formula I
For：Wherein, R1It is Cl or Br；Formula II isWherein, R2It is methyl and/or ethyl
And/or benzyl.
3. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1 or 2, it is characterised in that described halo is anti-
Should, the halogenating agent for using is NCS or NBS；Halogenating agent is 1~2 with the molar ratio of the chloro- 2- toluene fluorides of 4-:1.
4. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1 or 2, it is characterised in that described halo is anti-
Should, in the course of reaction, initiator and solvent being additionally added, initiator is azodiisobutyronitrile；Solvent is carbon tetrachloride.
5. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1 or 2, it is characterised in that described nucleophilic takes
Generation reaction, the nucleopilic reagent for using is diethyl malonate, dimethyl malenate or malonic acid dibenzyl ester；Nucleopilic reagent and formula
The molar ratio of I is 1~1.2:1.
6. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1 or 2, it is characterised in that described nucleophilic takes
Generation reaction, in the course of reaction, has been additionally added alkali and solvent, alkali be sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or
Caustic alcohol；Solvent is tetrahydrofuran or DMF.
7. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 6, it is characterised in that described alkali, itself and 4-
The molar ratio of chloro- 2- toluene fluorides is 1~2:1.
8. the preparation method of the fluoro- benzenpropanoic acids of the chloro- 2- of 4- as claimed in claim 1 or 2, it is characterised in that described hydrolysis takes off
Carboxylic reacts, and the solvent that it is used is ethanol, methyl alcohol or isopropanol；The alkali for using for sodium hydroxide solution, potassium hydroxide solution or
Lithium hydroxide solution.
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| CN101591232A (en) * | 2009-06-26 | 2009-12-02 | 湖南斯派克生物化工有限公司 | The preparation method of 3-(3-halogenophenyl) propionic acid |
| CN104592006A (en) * | 2015-01-23 | 2015-05-06 | 郑州大学 | Synthesis method of phenylpropionic acid compound |
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| CN101591232A (en) * | 2009-06-26 | 2009-12-02 | 湖南斯派克生物化工有限公司 | The preparation method of 3-(3-halogenophenyl) propionic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108358783A (en) * | 2018-04-13 | 2018-08-03 | 华烁科技股份有限公司 | The preparation method of 3- substituent glutaric acids diester and glutaconate diester |
| CN108358783B (en) * | 2018-04-13 | 2021-04-06 | 华烁科技股份有限公司 | 3-substituted glutaric diester and preparation method of glutaconic diester |
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