CN107673951A - A kind of high efficiency preparation method of 2,4,5 trifluoro benzene acetic acid - Google Patents
A kind of high efficiency preparation method of 2,4,5 trifluoro benzene acetic acid Download PDFInfo
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- CN107673951A CN107673951A CN201710710596.8A CN201710710596A CN107673951A CN 107673951 A CN107673951 A CN 107673951A CN 201710710596 A CN201710710596 A CN 201710710596A CN 107673951 A CN107673951 A CN 107673951A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/35—Preparation of halogenated hydrocarbons by reactions not affecting the number of carbon or of halogen atoms in the reaction
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
- C07C17/12—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms in the ring of aromatic compounds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- 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 invention discloses a kind of high efficiency preparation method of 2,4,5 trifluoro benzene acetic acids, belong to the synthesis technical field of medicine intermediate.Technical scheme main points are：The steps such as a kind of high efficiency preparation method of 2,4,5 trifluoro benzene acetic acids, including 2, the synthesis of 3,5 trifluoromethyl anilines, 1, the synthesis of 2,4 trifluoro-benzenes, the synthesis of trifluorobromobenzene and the synthesis of the trifluoro benzene acetic acid of target product 2,4,5.Operation is simple, raw material is cheap and easy to get, reaction efficiency is high and reproducible for present invention kind.
Description
Technical field
The invention belongs to the synthesis technical field of medicine intermediate, and in particular to one kind 2,4,5- trifluoro benzene acetic acids it is efficient
Preparation method.
Background technology
2,4,5- trifluoro benzene acetic acids be synthesize sitagliptin important intermediate, sitagliptin（Sitagliptin, commodity
Name Januvia）The first dipeptidyl peptidase (DPP)-IV inhibitor class that listing in 2006 is developed in for Merck companies of the U.S. resists
Rezulin, it is mainly used in the treatment of type ii diabetes.Sitagliptin is primarily directed to the insulin during type ii diabetes
Resistance and pancreatic islet alpha, the dysfunction of β cells, slow down incretin GLP-l degraded by suppressing DPP-IV, so as to play
Blood sugar reducing function.Because mechanism of action is novel, curative for effect, Small side effects, have become clinical best-selling antidiabetic medicine
One of, global annual sales amount is more than 2,000,000,000 dollars, good market prospect.The quality and price of 2,4,5- trifluoro benzene acetic acid qualities
Height have critically important influence for the quality and production cost of sitagliptin, therefore, to 2,4,5- trifluoro benzene acetic acids close
Into research tool have very important significance.
At present, the synthetic route for 2,4, the 5- trifluoro benzene acetic acids that document is reported mainly has following several method：1st, with 1,
2,4- trifluoro-benzenes are that raw material is made by chloromethylation, cyaniding, hydrolysis, and the synthetic route chloromethylation corrosivity is strong, dirty
Dye is serious, and needs to use hypertoxic cyanide, and technique has certain potential safety hazard；2nd, 2,4,5- trifluorobromobenzenes and malonic acid two
Ethyl ester is condensed to yield 2,4,5- trifluorophenyl diethyl malonates under sodium tert-butoxide and stannous chloride effect, then through sodium hydroxide
2,4,5- trifluoro benzene acetic acids are made in hydrolysis, hydrochloric acid acidifying, heating decarboxylation, and this method product yield is very high, but the reaction of bromine is lived
Property it is relatively low, it is necessary to a large amount of stannous chlorides catalysis, and sodium tert-butoxide price is higher；3rd, RMgBr is made in 2,4,5- trifluorobromobenzenes
Afterwards, coupling reaction is carried out with allyl bromide, bromoallylene, then double bond aoxidizes to obtain 2,4,5- trifluoro benzene acetic acids, and oxidant used in this method is
Ruthenium and sodium metaperiodate composite oxidant, cost of material are more expensive；4th, 2,4,5- trifluoro benzyls are obtained by 1,2,4- trifluoro-benzene chloromethylations
Chlorine, then form corresponding RMgBr and obtain 2,4,5- trifluoro benzene acetic acids, this method RMgBr with carbon dioxide reaction again
Preparation very high is required to reaction condition, and the shortcomings that chloromethylation three wastes are more still be present.
The content of the invention
Present invention solves the technical problem that there is provided one kind, operation is simple, raw material is cheap and easy to get, reaction efficiency is high
And the high efficiency preparation method of reproducible 2,4,5- trifluoro benzene acetic acids.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, the efficient system of one kind 2,4,5- trifluoro benzene acetic acids
Preparation Method, it is characterised in that concretely comprise the following steps：
（1）Aniline is added in glacial acetic acid, natrium nitrosum is added in 10 DEG C, then the aqueous solution of sodium fluoborate is added dropwise, in 10 DEG C
Filtered after reaction, add ethyl acetate extractive reaction liquid, organic phase uses the aqueous solution and pure water of sodium fluoborate successively, most
After be evaporated organic phase and obtain 2,3,5- trifluoromethyl anilines；
（2）2,3,5- trifluoromethyl anilines are added in the dilution heat of sulfuric acid that mass concentration is 10%, add reaction stabilizer pyrrole
Pyridine, in the hypophosphorous acid solution that sodium nitrite solution is added dropwise in room temperature successively and mass concentration is 50%, then with chloroform extractive reaction
Liquid, organic phase are evaporated to obtain 1,2,4- trifluoro-benzenes；
（3）1,2,4- trifluoro-benzene and lewis acid are added in glacial acetic acid, wherein lewis acid is alchlor, four chlorinations
Tin, neodymium trichloride-polystyrene complex or butter of tin-polystyrene complex, bromine is added dropwise in room temperature, reacts to TLC
Decompression steams glacial acetic acid after monitoring raw material reaction completely, adds chloroform, then washed with the dilute hydrochloric acid solution that mass concentration is 3%
Machine phase, then add saturated sodium bisulfite solution remove organic phase in bromine, and washed successively, saturated common salt water washing and
Trifluorobromobenzene is obtained after steaming solvent；Or by 1,2,4- trifluoro-benzenes and dibenzoyl peroxide（BPO）It is added to carbon tetrachloride
In, positioning catalyst molybdenum trioxide is added, N-bromosuccinimide is added in 0-5 DEG C（NBS）, add anti-after room temperature
Should, the complete rear plus water of TLC monitoring raw material reactions simultaneously separates organic phase, aqueous phase carbon tetrachloride extraction, and organic phase is concentrated to give three
Bromofluorobenzene；
（4）NaH is added in dioxane, diethyl malonate, CuBr and trifluorobromobenzene is added in 55-60 DEG C, is again heated to
110 DEG C of reactions, steam 3/4 solvent after having reacted, add sodium hydroxide solution, back flow reaction 3h, and whole is evaporated off after terminating in reaction
Solvent, it is dissolved in water, MTBE extracting impurities, aqueous phase, to 1-2, then carries out MTBE extractions, washing, saturation successively with salt acid for adjusting pH
Salt is washed, dry, filter, is evaporated to obtain Tan solid, and the Tan solid is in isopropyl ether with being passed through after activated carbon decolorizing
Filter, be recrystallized to give target product 2,4,5- trifluoro benzene acetic acids.
Further preferably, step（1）Described in aniline, natrium nitrosum and sodium fluoborate molar ratio be 1:1.2:
3.6。
Further preferably, step（2）Described in 2,3,5- trifluoromethyl anilines, dilution heat of sulfuric acid, pyridine and natrium nitrosum throwing
Material proportioning is 15g:100mL:10mL:20g.
Further preferably, step（3）Described in the charge ratio of 1,2,4- trifluoro-benzenes, lewis acid and bromine be 100g:
3-5g:127mL。
Further preferably, step（3）Described in 1,2,4- trifluoro-benzenes, dibenzoyl peroxide, molybdenum trioxide and N- bromos
The mass ratio that feeds intake of succinimide is 130:10:3:195.
Further preferably, step（4）Described in trifluorobromobenzene, diethyl malonate, NaH and CuBr molar ratio be
0.75:1.8:2.4:0.14。
Operation is simple, raw material is cheap and easy to get, reaction efficiency is high and reproducible for present invention kind.
Embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
By aniline 9.3g（0.1mol）It is added in glacial acetic acid 50mL, natrium nitrosum 8.2g is added in 10 DEG C（0.12mol）, then delay
Slowly it is added dropwise dissolved with sodium fluoborate 40g（0.36mol）Aqueous solution 50mL, keeping temperature is constant, react a period of time after filter, then
Add ethyl acetate 100mL extractive reactions liquid three times, merge organic phase, organic phase successively with the aqueous solution 10mL of sodium fluoborate and
Pure water 50mL is washed, and is finally evaporated organic phase and is obtained 2,3,5- trifluoromethyl aniline 13g.
Embodiment 2
By 2,3,5- trifluoromethyl anilines 15g（0.1mol）It is added in the dilution heat of sulfuric acid 100mL that mass concentration is 10%, adds
Pyridine 10mL, reaction temperature keep room temperature, natrium nitrosum 20g are slowly added dropwise（0.3mol）Solution, room temperature is kept not after dripping
Become, the hypophosphorous acid solution 20mL that mass concentration is 50% is added dropwise, steamed after merging organic phase with chloroform 100mL extractive reactions liquid three times
It is dry to obtain 1,2,4- trifluoro-benzenes 95g.
Embodiment 3
1,2,4- trifluoro-benzene 100g and alchlor 5g are added into 500mL there-necked flask, glacial acetic acid is as reaction dissolvent, in room
Bromine 127mL is slowly added dropwise under temperature, 2h is reacted after being added dropwise, TLC monitoring raw material reactions are complete, remove glacial acetic acid under reduced pressure, add
Enter chloroform 500mL, then organic phase is washed with the watery hydrochloric acid that mass concentration is 3%, add saturated sodium bisulfite solution and remove organic phase
In bromine, and washed successively, saturated common salt water washing, be evaporated off obtaining 152g product trifluorobromobenzenes after solvent, yield 95%,
It is 99.5% with gas chromatographic detection purity.
Embodiment 4
1,2,4- trifluoro-benzene 100g and butter of tin 5g are added into 500mL there-necked flask, glacial acetic acid is as reaction dissolvent, in room
Bromine 127mL is slowly added dropwise under temperature, 2h is reacted after being added dropwise, TLC monitoring raw material reactions are complete, remove glacial acetic acid under reduced pressure, add
Enter chloroform 500mL, then organic phase is washed with the watery hydrochloric acid that mass concentration is 3%, add saturated sodium bisulfite solution and remove organic phase
In bromine, and washed successively, saturated common salt water washing, solvent is evaporated off after obtain 158g product trifluorobromobenzenes, yield
98.7%, it is 99.2% with gas chromatographic detection purity.
Embodiment 5
1,2,4- trifluoro-benzene 100g and butter of tin-polystyrene complex 3g are added into 500mL there-necked flask, glacial acetic acid is made
For reaction dissolvent, bromine 127mL is slowly added dropwise at room temperature, 2h is reacted after being added dropwise, TLC monitoring raw material reactions are complete, subtract
Glacial acetic acid is evaporated off in pressure, adds chloroform 500mL, then washs organic phase with the watery hydrochloric acid that mass concentration is 3%, adds saturation sulfurous acid
Sodium solution remove organic phase in bromine, and washed successively, saturated common salt water washing, solvent is evaporated off after obtain 158g products three
Bromofluorobenzene, yield 98.7%, it is 99.6% with gas chromatographic detection purity.
Embodiment 6
In 1000mL reaction bulbs, by 1,2,4- trifluoro-benzene 130g（1mol）It is added to BPO 10g in carbon tetrachloride 300mL,
Molybdenum trioxide 3g is added, reaction temperature is set to 0-5 DEG C, is slow added into dissolved with NBS 195g（1.1mol）Tetrahydrofuran it is molten
Liquid 700mL, reaction is warmed to room temperature after adding, TLC monitoring raw material reactions are complete, add water 1000mL, separate organic phase, aqueous phase is again
With carbon tetrachloride 500mL extractions three times, trifluorobromobenzene 196g, yield 93.3% are concentrated to give after merging organic phase.
Embodiment 7
NaH is added in the reaction bulb containing dioxane 600mL（57.8g 2.4mol）, and malonic acid diethyl is added dropwise in 65 DEG C
Ester（288g, 1.8mol）, add CuBr（20.7g 0.14mol）And trifluorobromobenzene（158g, 0.75mol）, it is heated to 110 DEG C
20h is reacted, 3/4 solvent is boiled off after having reacted, adds the hydrolysis of 300mL sodium hydroxide solutions, back flow reaction 3h, reaction is steamed after terminating
Except whole solvents, be dissolved in water, MTBE extracting impurities, aqueous phase salt acid for adjusting pH to 1-2, carry out successively MTBE extractions, washing,
Saturated common salt is washed, dries, filters, being evaporated to obtain 130g Tan solids, and Tan solid is used into activated carbon in isopropyl ether
Decolourize and filter while hot, be recrystallized to give the trifluoro benzene acetic acid 130g of target product 2,4,5-, yield 95%, use liquid chromatographic detection
Purity is 99%.
Embodiment above describes the general principle of the present invention, main features and advantages, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (6)
1. one kind 2,4, the high efficiency preparation method of 5- trifluoro benzene acetic acids, it is characterised in that concretely comprise the following steps：
（1）Aniline is added in glacial acetic acid, natrium nitrosum is added in 10 DEG C, then the aqueous solution of sodium fluoborate is added dropwise, in 10 DEG C
Filtered after reaction, add ethyl acetate extractive reaction liquid, organic phase uses the aqueous solution and pure water of sodium fluoborate successively, most
After be evaporated organic phase and obtain 2,3,5- trifluoromethyl anilines；
（2）2,3,5- trifluoromethyl anilines are added in the dilution heat of sulfuric acid that mass concentration is 10%, add reaction stabilizer pyrrole
Pyridine, in the hypophosphorous acid solution that sodium nitrite solution is added dropwise in room temperature successively and mass concentration is 50%, then with chloroform extractive reaction
Liquid, organic phase are evaporated to obtain 1,2,4- trifluoro-benzenes；
（3）1,2,4- trifluoro-benzene and lewis acid are added in glacial acetic acid, wherein lewis acid is alchlor, four chlorinations
Tin, neodymium trichloride-polystyrene complex or butter of tin-polystyrene complex, bromine is added dropwise in room temperature, reacts to TLC
Decompression steams glacial acetic acid after monitoring raw material reaction completely, adds chloroform, then washed with the dilute hydrochloric acid solution that mass concentration is 3%
Machine phase, then add saturated sodium bisulfite solution remove organic phase in bromine, and washed successively, saturated common salt water washing and
Trifluorobromobenzene is obtained after steaming solvent；Or 1,2,4- trifluoro-benzene and dibenzoyl peroxide are added in carbon tetrachloride, then
Positioning catalyst molybdenum trioxide is added, N-bromosuccinimide is added in 0-5 DEG C, is added former after room temperature reaction, TLC monitoring
Add water after material reaction completely and separate organic phase, aqueous phase carbon tetrachloride extraction, organic phase is concentrated to give trifluorobromobenzene；
（4）NaH is added in dioxane, diethyl malonate, CuBr and trifluorobromobenzene is added in 55-60 DEG C, is again heated to
110 DEG C of reactions, steam 3/4 solvent after having reacted, add sodium hydroxide solution, back flow reaction 3h, and whole is evaporated off after terminating in reaction
Solvent, it is dissolved in water, MTBE extracting impurities, aqueous phase, to 1-2, then carries out MTBE extractions, washing, saturation successively with salt acid for adjusting pH
Salt is washed, dry, filter, is evaporated to obtain Tan solid, and the Tan solid is in isopropyl ether with being passed through after activated carbon decolorizing
Filter, be recrystallized to give target product 2,4,5- trifluoro benzene acetic acids.
2. according to claim 12, the high efficiency preparation method of 4,5- trifluoro benzene acetic acids, it is characterised in that：Step（1）In
The molar ratio of the aniline, natrium nitrosum and sodium fluoborate is 1:1.2:3.6.
3. according to claim 12, the high efficiency preparation method of 4,5- trifluoro benzene acetic acids, it is characterised in that：Step（2）In
The 2,3,5- trifluoromethyl anilines, dilution heat of sulfuric acid, the charge ratio of pyridine and natrium nitrosum are 15g:100mL:10mL:20g.
4. according to claim 12, the high efficiency preparation method of 4,5- trifluoro benzene acetic acids, it is characterised in that：Step（3）In
The charge ratio of the 1,2,4- trifluoro-benzenes, lewis acid and bromine is 100g:3-5g:127mL.
5. according to claim 12, the high efficiency preparation method of 4,5- trifluoro benzene acetic acids, it is characterised in that：Step（3）In
The 1,2,4- trifluoro-benzenes, dibenzoyl peroxide, the mass ratio that feeds intake of molybdenum trioxide and N-bromosuccinimide is 130:
10:3:195。
6. according to claim 12, the high efficiency preparation method of 4,5- trifluoro benzene acetic acids, it is characterised in that：Step（4）In
The trifluorobromobenzene, diethyl malonate, NaH and CuBr molar ratio are 0.75:1.8:2.4:0.14.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
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| CN113004142A (en) * | 2020-12-28 | 2021-06-22 | 台州达辰药业有限公司 | Novel preparation method of 2,4, 5-trifluoro-phenylacetic acid |
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Application publication date: 20180209 |