CN103214413A - Heterocycle-containing trifluoromethyl ketone compound and preparation method thereof - Google Patents
Heterocycle-containing trifluoromethyl ketone compound and preparation method thereof Download PDFInfo
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- CN103214413A CN103214413A CN2013100965202A CN201310096520A CN103214413A CN 103214413 A CN103214413 A CN 103214413A CN 2013100965202 A CN2013100965202 A CN 2013100965202A CN 201310096520 A CN201310096520 A CN 201310096520A CN 103214413 A CN103214413 A CN 103214413A
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Abstract
The invention discloses a heterocycle-containing trifluoromethyl ketone compound and a preparation method thereof. The trifluoromethyl ketone compound is a heterocyclic compound having R1, R2 and trifluoroacetyl. The heterocycle of the heterocyclic compound is of pyridine, pyrimidine, pyridazine, benzothiophene or benzofuran. The preparation method includes: 1) dissolving the heterocyclic compound containing R1, R2 and R3 in a solvent, adding an organolithium reagent in the presence of an inert gas, and reacting at -78 to -10 DEG C to get an organolithium intermediate; and 2) adding N-trifluoroacetylmorpholine to the organolithium intermediate in the step 1), reacting at -78-0 DEG C for a period, quenching the reaction by a quencher, and separating the reaction product. The heterocycle-containing trifluoromethyl ketone compound can be used as an enzyme inhibitor. The preparation method of the present invention can synthesize the heterocycle-containing trifluoromethyl ketone compound in one step, is simple to operate and high in yield, and has a wide application range.
Description
Technical field
The invention belongs to the organism synthesis technical field, be specifically related to a kind of heterocyclic trifluoromethyl ketone compound and preparation method thereof that contains.
Background technology
The trifluoromethyl ketone compound is because of being that effective enzyme inhibitors causes increasing concern.At present, the method that trifluoroacetyl group is introduced directly into organic molecule has a lot, for example: 1) pay the gram acylation reaction; 2) reaction of organometallic reagent and trifluoroacetic acid derivative; 3) carboxylicesters and TMS-CF
3Reaction; 4) Cd (CF
3)
2/ RCOCl and AgCF
3/ RCOCl system; 5) palladium catalysis cross-coupling reaction.But the most traditional and useful method is the reaction of organometallic reagent and trifluoroacetic acid derivative.
In the prior art, 1956, Dishart and Levine reported first were reacted one-step synthesis trifluoromethyl ketone compound with Grignard reagent and trifluoroacetic acid, still, and a large amount of excessive Grignard reagents of this reaction needed.1987, Creary obtained the alkyl of higher yields and the trifluoromethyl ketone compound that phenyl replaces with Trifluoroacetic Acid Ethyl Ester and Grignard reagent or organolithium reagent reaction.As far back as 1971, Salvador made the trifluoromethyl ketone compound with trifluoroacetamide and organometallic reagent reaction.But this class reaction is further studied, and does not have preparation to have the common method of substituent pyridine and relevant heterocyclic trifluoromethyl ketone compound so far.
Summary of the invention
What the purpose of this invention is to provide that a kind of potential can be as enzyme inhibitors contains heterocyclic trifluoromethyl ketone compound.
Another object of the present invention provides a kind of preparation method who contains heterocyclic trifluoromethyl ketone compound, and one-step synthesis contains heterocyclic trifluoromethyl ketone compound, and is simple to operate, the productive rate height.
In order to realize above purpose, the technical solution adopted in the present invention is: a kind of heterocyclic trifluoromethyl ketone compound that contains, and the structural formula of described trifluoromethyl ketone compound is:
Wherein: R
1Be fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, t-butoxycarbonyl amino or hydrogen, R
2Be fluorine, chlorine, bromine, methyl, ethyl, methoxyl group or t-butoxycarbonyl amino.
In formula 4 and the formula 5, the replacement position of trifluoroacetyl group is a two or three-digit, R
1And R
2The replacement position be 4,5,6 or 7.
A kind of preparation method who contains heterocyclic trifluoromethyl ketone compound comprises the following steps:
1) will have R
1, R
2And R
3Heterogeneous ring compound be dissolved in the solvent, under protection of inert gas, add organolithium reagent, the mol ratio that makes elemental lithium and heterogeneous ring compound is (10～30): (5～10), under-78～-10 ℃ of conditions, react 0.5～4h, the organolithium intermediate;
2) in step 1) gained organolithium intermediate, add N-TFA base morpholine, make the mol ratio of the heterogeneous ring compound that adds in N-TFA base morpholine and the step 1) be (10～15): (5～10), under-78～0 ℃ of condition, react 0.5～2h, react with the quencher cancellation under-78 ℃～20 ℃ conditions the back, reaction product is separated, promptly;
Wherein, the heterocyclic type of described heterogeneous ring compound is pyridine, pyrimidine, pyridazine, thionaphthene or cumarone, R
3Be bromine or hydrogen.
Described organolithium reagent is n-Butyl Lithium (n-BuLi) or is made by following method:
At-78～0 ℃, under the protection of inert gas, with close lithium organism be dissolved in the solvent mixing solutions; at gained mixed solution and dripping n-Butyl Lithium; make n-Butyl Lithium and the organic mol ratio of close lithium be (10～30): (10～24.2), react 30～40min down at 0 ℃, promptly.
Described close lithium organism is a diisopropylamine (LDA), 2,2,6,6-tetramethyl piperidine (TMP), Tetramethyl Ethylene Diamine (TMEDA) and N, any one in the N-dimethylethanolamine (DMEA).
Described solvent is any one or the combination in toluene, normal hexane, ether, tetrahydrofuran (THF) (THF) and the 2-methyltetrahydrofuran.
Described quencher is water or saturated ammonium chloride solution.
Step 2) isolating method is described in: reaction product is merged organic phase with extraction agent extraction back, this organic phase drying, filter, be spin-dried for after, carry out column chromatography and separate.
Described extraction agent is an ethyl acetate; It is with sherwood oil that described column chromatography is separated: ethyl acetate=2:1～40:1 is a developping agent.
Described N-TFA base morpholine is prepared by following method:
A. under the ice-water bath condition, add trifluoroacetic anhydride in the mixed solution of morpholine and triethylamine, the mol ratio that makes trifluoroacetic anhydride, morpholine and triethylamine is 11:10:10, behind 0 ℃ of reaction 30min, temperature is risen to stirred overnight at room temperature, gets reaction product;
B. step a gained reaction product is added water, with merging organic phase after the extracted with diethyl ether, this organic phase drying, filter, be spin-dried for after, be that developping agent carries out column chromatography and separates with sherwood oil: ethyl acetate=5:1～10:1, promptly.
The heterocyclic trifluoromethyl ketone compound that contains of the present invention is for having trifluoroacetyl group and R
1, R
2Heterogeneous ring compound, be not only the potential enzyme inhibitors, the still synthetic important intermediate that contains trifluoromethyl heterocycle compound and other fluorochemicalss; In addition, it also is the monomer of novel macromolecular material, and therefore, it has purposes widely at medicine and polymeric material field.
The preparation method who contains heterocyclic trifluoromethyl ketone compound of the present invention, to contain substituent heterogeneous ring compound is raw material, with various organolithium reagents is lithiation reagent, with N-TFA base morpholine is fluorination reagent, one-step synthesis contains heterocyclic trifluoromethyl ketone compound, this method is simple to operate, the productive rate height; Used fluorination reagent is stablized, is easy to get, and cost is lower; Preparation method of the present invention has extensive applicability, is fit to large-scale industrial production.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1
The heterocyclic trifluoromethyl ketone compound that contains of present embodiment is 2-trifluoroacetyl group-5-bromopyridine.Band R
1, R
2, R
3Heterogeneous ring compound be 2,5-dibromo pyridine, wherein R
1Be hydrogen, R
2Be bromine (5), R
3Be bromine (2) that the heterocyclic type of heterogeneous ring compound is a pyridine.
The preparation method who contains heterocyclic trifluoromethyl ketone compound of present embodiment comprises the following steps:
1) with 2 of 10mmol, the 5-dibromo pyridine is dissolved in the 20ml toluene, and slow dropping organolithium reagent under nitrogen protection (n-BuLi, 11mmol), 2h is reacted in the back under-78 ℃ of conditions, gets the organolithium intermediate;
2) the slow N-TFA base morpholine that drips 15mmol in step 1) gained organolithium intermediate reacts 2h under-78 ℃ of conditions, and temperature is risen to room temperature naturally; stirring is spent the night;, separate reaction product, promptly as quencher cancellation reaction at 20 ℃ of water of using 10ml down the back.
Among the preparation method who contains heterocyclic trifluoromethyl ketone compound of present embodiment, step 2) isolating method is described in: reaction product is merged organic phase after with ethyl acetate extraction, and this organic phase is through anhydrous MgSO
4After the drying, filtering, be spin-dried for, is that developping agent carries out the column chromatography separation with sherwood oil: ethyl acetate=20:1.
Among the preparation method who contains heterocyclic trifluoromethyl ketone compound of present embodiment, used N-TFA base morpholine is prepared by following method:
A. under the ice-water bath condition, in the mixed solution of the triethylamine of the morpholine of 0.5mol and 0.5mol, drip the trifluoroacetic anhydride of 0.55mol, behind 0 ℃ of reaction 30min, temperature risen to stirred overnight at room temperature, reaction product;
B. step a gained reaction product is added water 200ml, with merging organic phase after the extracted with diethyl ether, this organic phase is through anhydrous MgSO
4After the drying, filtering, be spin-dried for, is that developping agent carries out the column chromatography separation with sherwood oil: ethyl acetate=5:1, promptly.
The structure that contains heterocyclic trifluoromethyl ketone compound of embodiment 2～26 is as shown in table 1.
The preparation method's who contains heterocyclic trifluoromethyl ketone compound of embodiment 2～26 step is with embodiment 1, and wherein raw materials used, reagent and consumption are as shown in table 2, and organolithium reagent is as shown in table 3, and conditional parameter is as shown in table 4.
The structure that contains heterocyclic trifluoromethyl ketone compound of table 1 embodiment 1～26 (being the replacement position in the bracket)
The preparation method's who contains heterocyclic trifluoromethyl ketone compound of table 2 embodiment 1～26 raw material, reagent and consumption
The organolithium reagent of table 3 embodiment 1～26
The preparation method's who contains heterocyclic trifluoromethyl ketone compound of table 4 embodiment 1～26 conditional parameter
Experimental example
This experimental example has detected preparation method's the product yield of the trifluoromethyl ketone compound of embodiment 1～26, and preparation method's products obtained therefrom of the trifluoromethyl ketone compound of embodiment 1～26 has been carried out the nuclear-magnetism sign, and the result is as shown in table 5.
The preparation method's of the trifluoromethyl ketone compound of table 5 embodiment 1～26 product yield and nuclear-magnetism characterize.
Claims (10)
1. one kind contains heterocyclic trifluoromethyl ketone compound, and it is characterized in that: the structural formula of described trifluoromethyl ketone compound is:
Wherein: R
1Be fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, t-butoxycarbonyl amino or hydrogen, R
2Be fluorine, chlorine, bromine, methyl, ethyl, methoxyl group or t-butoxycarbonyl amino.
2. the heterocyclic trifluoromethyl ketone compound that contains according to claim 1 is characterized in that: in formula 4 and the formula 5, the replacement position of trifluoroacetyl group is a two or three-digit, R
1And R
2The replacement position be 4,5,6 or 7.
3. a preparation method who contains heterocyclic trifluoromethyl ketone compound as claimed in claim 1 is characterized in that: comprise the following steps:
1) will have R
1, R
2And R
3Heterogeneous ring compound be dissolved in the solvent, under protection of inert gas, add organolithium reagent, the mol ratio that makes elemental lithium and heterogeneous ring compound is (10～30): (5～10), under-78～-10 ℃ of conditions, react 0.5～4h, the organolithium intermediate;
2) in step 1) gained organolithium intermediate, add N-TFA base morpholine, make the mol ratio of the heterogeneous ring compound that adds in N-TFA base morpholine and the step 1) be (10～15): (5～10), under-78～0 ℃ of condition, react 0.5～2h, react with the quencher cancellation under-78 ℃～20 ℃ conditions the back, reaction product is separated, promptly;
Wherein, the heterocyclic type of described heterogeneous ring compound is pyridine, pyrimidine, pyridazine, thionaphthene or cumarone, R
3Be bromine or hydrogen.
4. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 3 is characterized in that: described organolithium reagent is n-Butyl Lithium or is made by following method:
At-78～0 ℃, under the protection of inert gas, with close lithium organism be dissolved in the solvent mixing solutions; at gained mixed solution and dripping n-Butyl Lithium; make n-Butyl Lithium and the organic mol ratio of close lithium be (10～30): (10～24.2), react 30～40min down at 0 ℃, promptly.
5. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 4, it is characterized in that: described close lithium organism is a diisopropylamine, 2,2,6,6-tetramethyl piperidine, Tetramethyl Ethylene Diamine and N, any one in the N-dimethylethanolamine.
6. according to claim 3 or the 4 described preparation methods that contain heterocyclic trifluoromethyl ketone compound, it is characterized in that: described solvent is any one or the combination in toluene, normal hexane, ether, tetrahydrofuran (THF) and the 2-methyltetrahydrofuran.
7. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 3 is characterized in that: described quencher is water or saturated ammonium chloride solution.
8. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 3, it is characterized in that: step 2) described in isolating method be: reaction product is merged organic phase with extraction agent extraction back, this organic phase drying, filter, be spin-dried for after, carry out column chromatography and separate.
9. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 8 is characterized in that: described extraction agent is an ethyl acetate; It is with sherwood oil that described column chromatography is separated: ethyl acetate=2:1～40:1 is a developping agent.
10. the preparation method who contains heterocyclic trifluoromethyl ketone compound according to claim 3 is characterized in that: described N-TFA base morpholine is prepared by following method:
A. under the ice-water bath condition, add trifluoroacetic anhydride in the mixed solution of morpholine and triethylamine, the mol ratio that makes trifluoroacetic anhydride, morpholine and triethylamine is 11:10:10, behind 0 ℃ of reaction 30min, temperature is risen to stirred overnight at room temperature, gets reaction product;
B. step a gained reaction product is added water, with merging organic phase after the extracted with diethyl ether, this organic phase drying, filter, be spin-dried for after, be that developping agent carries out column chromatography and separates with sherwood oil: ethyl acetate=5:1～10:1, promptly.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503822A (en) * | 2015-12-16 | 2016-04-20 | 温州大学 | Preparation method for trifluoromethyl benzothiophene derivative and purification method for product of preparation method |
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Address after: 450000 Zhengzhou high tech Industrial Development Zone, Henan, Holly Street, No. 7 Patentee after: TETRANOV PHARMACY STOCK INC. Address before: 450052 No. 75, University Road, Zhengzhou, Henan Patentee before: Tetranov Biopharm, Inc. |
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Effective date of registration: 20201117 Address after: Room 1402-9, Changxing Taihu capital Plaza, No. 1278, Mingzhu Road, Changxing Economic Development Zone, Huzhou City, Zhejiang Province Patentee after: Zhejiang Yaoling Pharmaceutical Technology Co., Ltd Address before: 450000 Zhengzhou high tech Industrial Development Zone, Henan, Holly Street, No. 7 Patentee before: ZHENGZHOU TETRANOV PHARMACEUTICAL Co.,Ltd. |