CN105949201A - Synthesis method of 5-(4-fluorophenyl)-N-(4-chlorophenylethyl)-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide - Google Patents

Synthesis method of 5-(4-fluorophenyl)-N-(4-chlorophenylethyl)-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide Download PDF

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CN105949201A
CN105949201A CN201610349626.2A CN201610349626A CN105949201A CN 105949201 A CN105949201 A CN 105949201A CN 201610349626 A CN201610349626 A CN 201610349626A CN 105949201 A CN105949201 A CN 105949201A
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牛亚慧
石磊
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Chongqing Medical and Pharmaceutical College
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Chongqing Medical and Pharmaceutical College
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a synthesis method of 5-(4-fluorophenyl)-N-(4-chlorophenylethyl)-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide. The synthesis method includes: using arone which is low in cost and easy to obtain as a starting raw material; synthesizing arone and para-trifluoromethyl ethyl acetate into an intermediate-aryl butanedione, adding glacial acetic acid and aminopyrazol, and heating for backflow to generate a target intermediate; hydrolyzing to obtain 5-aryl-7-substitutent pyrazol[1, 5-a] pyrimidine acid, and obtaining a target product through condensation reaction. Through continuous reaction of condensation and cyclization, 5-(4-fluorophenyl)-N-(4-chlorophenylethyl)-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide is synthesized with high yield. The synthesis method is simple and convenient to operate and high in yield, and the product is easy to purify.

Description

5-(4-fluorophenyl)-N-(4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide
Technical field
The present invention relates to the field of chemical synthesis, specifically 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrrole The synthetic method of azoles also [1,5-a] pyrimidine-3-amide.
Background technology
There is in pyrazolo [1,5-a] pyrimidine derivatives molecule pyrazoles and the important activity unit of pyrimidine two class simultaneously, It is organic chemistry and the important nitrogen heterocyclic ring of pharmaceutical chemistry.
This compounds has biological activity and pharmacological action widely, and in prior art, research contents is less.
Pyrazolo [1,5-a] pyrimidines has diverse biological activities, can be used as antischistosomal drug, xanthine oxidation Enzyme inhibitor and ALS enzymatic synthesis inhibitor.Structure parent nucleus diverse location, pyrazolo [1,5-a] miazines of different substituents Compound has caused the concern of scientist.
Substantial amounts of research shows, pyrazole compound has weeding, parasite killing, antibacterium, antifungal and other multiple life Thing activity, the sedative hypnotic drugs zaleplon listed just belongs to this type of Hete rocyclic derivatives.
And it is more expensive to synthesize this type of heterocyclic derivatives raw material, and productivity is low, produce the product not easy purification of gained.
Summary of the invention
Present invention aim to address in prior art, synthesize 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-fluoroform The problem such as the synthesis material of base pyrazolo [1,5-a] pyrimidine-3-amide is more expensive, synthetic method is complicated and productivity is low.
Employed technical scheme comprise that such for realizing the object of the invention, 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)- The synthetic method of 7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide, it is characterised in that comprise the following steps:
1) synthetic intermediate 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester
1.1) ethyoxyl methene base nitrile ethyl acetate is joined equipped with in the container I of dehydrated alcohol, described (ethoxymethyl) Solid-liquid ratio (g mL) scope of fork base nitrile ethyl acetate and dehydrated alcohol is 1 10～1 5；
1.2), after hydrazine hydrate being added dropwise to container I, container I is placed in electric heating device, in the range of 30～60 minutes by Gradually it is warming up to 80 DEG C, obtains mixture A；Described hydrazine hydrate and step 1.1) in the mass ratio of dehydrated alcohol be 2:1；Or it is described Hydrazine hydrate and step 1.1) in ethyoxyl methene base nitrile ethyl acetate mass ratio be 2:1；
1.3) being heated to reflux by mixture A, after refluxing 3～5 hours, decompression distills out ethanol, remaining solid；
1.4) solid cooling is stood to separating out light yellow solid, light yellow solid is filtered, wash, be dried, in obtaining Mesosome 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester；
2) synthetic intermediate 1-is to fluorophenyl-4,4,4 ,-trifluoro diacetyl
2.1) toluene and dehydrated alcohol are placed in container II, obtain mixture B；Anhydrous in described toluene and this step The volume range of ethanol is 1 10～1 1；
2.2) metallic sodium of chopping is put into equipped with in the container II of mixture B, stir and white powder occurs to container II End, and without sodium remain after, container II is placed under cooling condition；Solid-liquid ratio (g mL) model of described metallic sodium and mixture B Enclose is 1 5～1 1；
2.3) fluoro acetophenone and Trifluoroacetic Acid Ethyl Ester will be placed in container II, obtain mixture C, described to fluorophenethyl Ketone, Trifluoroacetic Acid Ethyl Ester and described step 2.2) in the mass ratio of metallic sodium be 321；
2.4) container II is placed in electric heating device, in the range of 30～45 minutes, is gradually heating to 60～65 DEG C, react 6 ～after 8 hours, carry out decompression and distill, extract, wash, merge organic facies, be dried, obtain mixture D；
2.5) mixture D is carried out decompression distillation and is placed under cooling condition standing, filter after separating out white solid, do Dry, obtain intermediate 1-to fluorophenyl-4,4,4 ,-trifluoro diacetyl；
3) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester
3.1) by step 1) in the 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester that obtains and step 2) in the 1-that obtains to fluorobenzene Base-4,4,4 ,-trifluoro diacetyl is placed in container III, described 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester and 1-to fluorophenyl-4, 4,4, the quality of-trifluoro diacetyl is 1 3～1 2 than scope；
3.2), after using glacial acetic acid to be dissolved by the mixture in container III, obtain mixture E, container III is placed in electric heating bar Under part, it is warming up to 115 DEG C～118 DEG C；The described 1-solid-liquid ratio (g to fluorophenyl-4,4,4 ,-trifluoro diacetyl and glacial acetic acid ML) scope is 5 2～10 2；
3.3) mixture E is heated to reflux, after 6～8 hours, cools down, stand, separate out yellow green tip-like solid；Will be solid Body filters, washing, dried, obtain 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester；
4) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid
4.1) NaOH is placed in the ethanol solution that concentration is 10%, obtains in mixture F, described NaOH and this step Solid-liquid ratio (g mL) scope of ethanol solution is 1 10～1 8；
4.2) by step 3) in 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid second of obtaining Ester is placed in the container IV at mixture F place, obtain mixture G, described 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1, 5-a] solid-liquid ratio (g mL) scope of pyrimidine-3-carboxylic acid, ethyl ester and mixture F is 1 2～1 1；
4.3) mixture G was gradually heating to 60～65 DEG C in the range of 30～45 minutes, after stirring 10～12 hours, cold But；Reacted mixture G is joined in mixture of ice and water, obtains mixture H, described mixture G and mixture of ice and water Volume range is 1 3～1 2；
4.4) pH value of mixture H is regulated to 1～2, after stirring 10～15 minutes, separate out Off-white solid, filter；
4.5) by step 4.4) in solid after the filtration that obtains adds acetonitrile, obtain pure solid 5-(4-fluorophenyl)- 7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid；Described step 4.4) in the matter of solid after the filtration that obtains and acetonitrile Amount ratio is 1:15～1:10；
5) derivant of 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine is synthesized
5.1) by step 4) in obtain 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, DMAP, I-hydroxybenzotriazole, to chlorophenethylamine, press Mass ratio according to 1111 or 1112 and order mix, and obtain mixture I；
5.2) carry out described mixture I place container V sealing, evacuation, logical nitrogen；
5.3) by described step 5.2) in triplicate after, under a nitrogen atmosphere, by oxolane that volume ratio is 13 and N, Dinethylformamide joins in mixture I, obtains mixture J；Described oxolane and N,N-dimethylformamide are Being dried anhydrous compound, solid-liquid ratio (g mL) scope of described mixture I and oxolane is 1 5～1 2；
5.4) being placed under electric heating environment by the container V at mixture J place, be warming up to 40～45 DEG C, reacting by heating 6～8 is little Shi Hou, carries out extracting, washes, is associated with sign, is dried, to mixture K；
5.5) mixture K is carried out decompression distillation, separates out solid；After the solid separated out is filtered, washed, obtain product；
6) dehydrated alcohol recrystallization
In step 5.5) in the product that obtains adds dehydrated alcohol, be placed in 80 degrees Celsius of environment after lower 2 hours, mixed Close solution；Mixed solution is placed in low temperature 2～8 DEG C, overnight, obtains pure products 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7- Trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide.
Further, described step 1.4) in washing process use article be cold dehydrated alcohol.
Further, described step 2.4) in extraction cross and be referred to as making to be extracted with ethyl acetate, and extraction process repeat 2～ 4 times；Described water-washing process repeats 2～4 times；Described dry run is dried for using anhydrous sodium sulfate.
Further, described step 3.3) in washing process use article be cold glacial acetic acid.
Further, described step 4.4) the middle hydrochloric acid that process is interpolation 1mol/L regulating pH value.
Further, described step 5.4) in extraction process for making to be extracted with ethyl acetate, and extraction process repeat 2～ 4 times；Described water-washing process repeats 2～4 times；Described dry run is dried for using anhydrous sodium sulfate.
Further, described step 5.5) in washing process be that the mixed liquor using ethyl acetate and normal hexane is washed Wash.
The solution have the advantages that mathematical, the present invention is with arone cheap and easy to get as initiation material, by contracting Close, cyclization two step continuous print reacts, and has synthesized a series of 5-aryl substituted pyrazolo [1,5-a] miazines with higher productivity Compound.Method used in the present invention is easy and simple to handle, and productivity is higher, and product is prone to purification.
Accompanying drawing explanation
Fig. 1 is 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide Synthetic route.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, but only should not be construed the above-mentioned subject area of the present invention It is limited to following embodiment.Without departing from the idea case in the present invention described above, according to ordinary skill knowledge with used By means, make various replacement and change, all should include within the scope of the present invention.
As it is shown in figure 1,5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3- The synthetic method of amide, it is characterised in that comprise the following steps:
1) synthetic intermediate 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester
1.1) ethyoxyl methene base nitrile ethyl acetate (68g, 0.4mol) is joined the container equipped with 200mL dehydrated alcohol In；
1.2) after 100mL hydrazine hydrate being added dropwise to container, container is placed in electric heating device, in the range of 30 minutes gradually It is warming up to 80 DEG C, obtains mixture A；
1.3) being heated to reflux by mixture A, after refluxing 4 hours, decompression distills out ethanol, remaining solid；
1.4) solid cooling is stood to separating out light yellow solid, light yellow solid is filtered, wash, be dried, in obtaining Mesosome 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester；The article that described washing process uses are cold dehydrated alcohol.
The quality of described product 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester is 41.68g.Yield: 66.78%
2) synthetic intermediate 1-is to fluorophenyl-4,4,4 ,-trifluoro diacetyl
2.1) 100mL toluene and dehydrated alcohol (16.56g, 0.36mol) are placed in container, obtain mixture B；
2.2) metallic sodium (8.28g, 0.36mol) of chopping is put in the container equipped with mixture B, stir to container Occur white powder, and without sodium remain after, container is placed under cooling condition；
2.3) fluoro acetophenone (41.4g, 0.3mol) and Trifluoroacetic Acid Ethyl Ester (51.12g, 0.36mol) will be placed in container In, obtain mixture C；
2.4) container is placed in electric heating device, in the range of 30 minutes, is gradually heating to 60 DEG C, after reacting 6 hours, enter Row decompression is distilled, extracts, washes, is merged organic facies, dry run, obtains mixture D；
Described extraction is referred to as making to be extracted with ethyl acetate, and extraction process is repeated 3 times；Described water-washing process repeats 2 Secondary；Described dry run is dried for using anhydrous sodium sulfate.
2.5) mixture D is carried out decompression distillation and is placed under cooling condition standing, filter after separating out white solid, do Dry, obtain intermediate 1-to fluorophenyl-4,4,4 ,-trifluoro diacetyl；
Described product 1-is to fluorophenyl-4,4,4, and the quality of-trifluoro diacetyl is 51.245g.Yield: 73.00%.
3) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester
3.1) by step 1) in 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester (15.5g, 0.1mol) that obtains and step 2) in The 1-obtained to fluorophenyl-4,4,4 ,-trifluoro diacetyl (23.4g, 0.1mol) is placed in container；
3.2), after using 50mL glacial acetic acid to be dissolved by the mixture in container, obtain mixture E, container is placed in electric heating bar Under part, it is warming up to 115 DEG C；
3.3) mixture E is heated to reflux, after 7 hours, cools down, stand, separate out yellow green tip-like solid；By solid mistake Filter, washing, dried, obtain 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester；Described wash The article that process of washing uses are cold glacial acetic acid.
The quality of products therefrom 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester is 27.05g.Yield: 76.63%.
4) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid
4.1) 5.6g NaOH is placed in the ethanol solution that concentration is 95%, obtains mixture F；
4.2) by step 3) in 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid second of obtaining Ester (20.202g, 57mmol) is placed in the container at mixture F place, obtains mixture G；
4.3) mixture G was gradually heating to 65 DEG C in the range of 30 minutes, after stirring 10 hours, cooling；After reacting Mixture G join in 300mL mixture of ice and water, obtain mixture H；
4.4) pH value of mixture H is regulated after 2, after stirring 15 minutes, separate out Off-white solid, filter；Described tune The process of joint pH value is to add the hydrochloric acid of 1mol/L.
4.5) by step 4.4) in solid after the filtration that obtains adds acetonitrile, obtain pure solid 5-(4-fluorophenyl)- 7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid；
The quality of products therefrom 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid is 8.748g.Yield: 47.03%.
5) derivant of 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine is synthesized
5.1) by step 4) in 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid of obtaining (1g, 3.08mmol), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (1.182g, 6.18mmol), 4-dimethylamino pyrrole Pyridine (0.385g, 3.08mmol), I-hydroxybenzotriazole (0.415g, 3.08mmol), to chlorophenethylamine (4.62mmol), carry out Mixing, obtains mixture I；
5.2) carry out described mixture I place container sealing, evacuation, logical nitrogen；
5.3) by described step 5.2) in triplicate after, under a nitrogen atmosphere, by 10mL oxolane and 30mL TN, N- Dimethylformamide joins in mixture I, obtains mixture J；Described oxolane and TN, dinethylformamide is dry Dry anhydrous compound；
5.4) being placed under electric heating environment by mixture J place container, be warming up to 40 DEG C, reacting by heating, after 6 hours, extracts Take, wash, be associated with sign, be dried, to mixture K；
Described extraction process is for making to be extracted with ethyl acetate, and extraction process is repeated 3 times；Described water-washing process repeats 2 Secondary；Described dry run is dried for using anhydrous sodium sulfate.
5.5) mixture K is carried out decompression distillation, separates out solid；After the solid separated out is filtered, washed, obtain product. Described washing process is that the mixed liquor using ethyl acetate and normal hexane washs.
6) dehydrated alcohol recrystallization
In step 5.5) in the product that obtains adds dehydrated alcohol, be placed in 80 degrees Celsius of environment after lower 2 hours, mixed Close solution；Mixed solution is placed in low temperature 2～8 DEG C, overnight, obtains pure products 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7- Trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide.
Product 5-(4-fluorophenyl)-N (4-the chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] obtained after purification is phonetic The quality of pyridine-3-amide is 0.683g.
Described step 1)～5) flow process as shown in Figure 1.
Described 5-aryl substituted pyrazolecarboxylic also [1,5-a] pyrimidine derivatives product 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)- Fusing point and the yield of 7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide are as shown in table 1.
Table 1
Described 5-aryl substituted pyrazolecarboxylic also [1,5-a] pyrimidine derivatives product 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)- The structural characterization data of 7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide are as shown in table 2.
Table 2

Claims (7)

  1. The synthesis side of 1.5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-amide Method, it is characterised in that comprise the following steps:
    1) synthetic intermediate 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester
    1.1) ethyoxyl methene base nitrile ethyl acetate is joined equipped with in the container I of dehydrated alcohol, described ethyoxyl methene base Solid-liquid ratio (g mL) scope of nitrile ethyl acetate and dehydrated alcohol is 1 10～1 5；
    1.2) after hydrazine hydrate being added dropwise to container I, container I is placed in electric heating device, gradually rose in the range of 30～60 minutes Temperature, to 80 DEG C, obtains mixture A；Described hydrazine hydrate and step 1.1) in the mass ratio of dehydrated alcohol be 2:1；
    1.3) being heated to reflux by mixture A, after refluxing 3～5 hours, decompression distills out ethanol, remaining solid；
    1.4) solid cooling is stood to separating out light yellow solid, light yellow solid is filtered, wash, be dried, obtain intermediate 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester；
    2) synthetic intermediate 1-is to fluorophenyl-4,4,4 ,-trifluoro diacetyl
    2.1) toluene and dehydrated alcohol are placed in container II, obtain mixture B；Dehydrated alcohol in described toluene and this step Volume range be 1 10～1 1；
    2.2) being put into by the metallic sodium of chopping equipped with in the container II of mixture B, there is white powder to container II in stirring, and And after remaining without sodium, container II is placed under cooling condition；Solid-liquid ratio (g mL) scope of described metallic sodium and mixture B is 1 5～1 1；
    2.3) fluoro acetophenone and Trifluoroacetic Acid Ethyl Ester will be placed in container II, obtain mixture C, described to fluoro acetophenone, three Ethyl fluoroacetate and described step 2.2) in the mass ratio of metallic sodium be 321；
    2.4) container II is placed in electric heating device, in the range of 30～45 minutes, is gradually heating to 60～65 DEG C, react 6～8 After hour, carry out decompression and distill, extract, wash, merge organic facies, be dried, obtain mixture D；
    2.5) mixture D is carried out decompression distillation and is placed under cooling condition standing, filter after separating out white solid, be dried, To intermediate 1-to fluorophenyl-4,4,4 ,-trifluoro diacetyl；
    3) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester
    3.1) by step 1) in the 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester that obtains and step 2) in the 1-that obtains to fluorophenyl- 4,4,4 ,-trifluoro diacetyl is placed in container III, described 5-amino-1H-pyrazoles-4-carboxylic acid, ethyl ester and 1-to fluorophenyl-4,4, 4, the quality of-trifluoro diacetyl is 1 3～1 2 than scope；
    3.2), after using glacial acetic acid to be dissolved by the mixture in container III, obtain mixture E, container III is placed in electric heating condition Under, it is warming up to 115 DEG C～118 DEG C；The described 1-solid-liquid ratio (g mL) to fluorophenyl-4,4,4 ,-trifluoro diacetyl and glacial acetic acid Scope is 5 2～10 2；
    3.3) mixture E is heated to reflux, after 6～8 hours, cools down, stand, separate out yellow green tip-like solid；By solid mistake Filter, washing, dried, obtain 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester；
    4) synthesis 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid
    4.1) NaOH is placed in the ethanol solution that concentration is 10%, obtains the ethanol in mixture F, described NaOH and this step Solid-liquid ratio (g mL) scope of solution is 1 10～1 8；
    4.2) by step 3) in 5-(4-the fluorophenyl)-7-trifluoromethyl pyrazol that obtains [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester put In the container IV at mixture F place, obtain mixture G, described 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] Pyrimidine-3-carboxylic acid, ethyl ester is 1 2～1 1 with solid-liquid ratio (g mL) scope of mixture F；
    4.3) mixture G was gradually heating to 60～65 DEG C in the range of 30～45 minutes, after stirring 10～12 hours, cooling； Reacted mixture G is joined in mixture of ice and water, obtains the volume of mixture H, described mixture G and mixture of ice and water It is 1 3～1 2 than scope；
    4.4) pH value of mixture H is regulated to 1～2, after stirring 10～15 minutes, separate out Off-white solid, filter；
    4.5) by step 4.4) in solid after the filtration that obtains adds acetonitrile, obtain pure solid 5-(4-fluorophenyl)-7-three Methyl fluoride pyrazolo [1,5-a] pyrimidine-3-carboxylic acid；Described step 4.4) in the mass ratio of solid after the filtration that obtains and acetonitrile For 1:15～1:10；
    5) derivant of 5-(4-fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine is synthesized
    5.1) by step 4) in 5-(4-the fluorophenyl)-7-trifluoromethyl pyrazol also [1,5-a] pyrimidine-3-carboxylic acid, the 1-(3-that obtain Dimethylamino-propyl)-3-ethyl carbodiimide, DMAP, I-hydroxybenzotriazole, to chlorophenethylamine, according to 1 The mass ratio of 111 or 1112 and order mix, and obtain mixture I；
    5.2) carry out described mixture I place container V sealing, evacuation, logical nitrogen；
    5.3) by described step 5.2) in triplicate after, under a nitrogen atmosphere, by oxolane that volume ratio is 13 and N, N-bis- Methylformamide joins in mixture I, obtains mixture J；Described oxolane and N,N-dimethylformamide are dry Anhydrous compound, solid-liquid ratio (g mL) scope of described mixture I and oxolane is 1 5～1 2；
    5.4) container V at mixture J place is placed under electric heating environment, is warming up to 40～45 DEG C, reacting by heating 6～8 hours After, carry out extracting, wash, be associated with sign, be dried, to mixture K；
    5.5) mixture K is carried out decompression distillation, separates out solid；After the solid separated out is filtered, washed, obtain product；
    6) dehydrated alcohol recrystallization
    In step 5.5) in the product that obtains adds dehydrated alcohol, be placed in 80 degrees Celsius of environment after lower 2 hours, obtain mixing molten Liquid；Mixed solution is placed in low temperature 2～8 DEG C, overnight, obtains pure products 5-(4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoro Methylpyrazole also [1,5-a] pyrimidine-3-amide.
  2. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 1.4) in the article that use of washing process be cold anhydrous Ethanol.
  3. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 2.4) in extraction cross and be referred to as making to be extracted with ethyl acetate, And extraction process repeats 2～4 times；Described water-washing process repeats 2～4 times；Described dry run is entered for using anhydrous sodium sulfate Row is dried.
  4. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 3.3) in washing process use article be cold ice second Acid.
  5. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 4.4) in regulation pH value process for add hydrochloric acid.
  6. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 5.4) in extraction process for making to be extracted with ethyl acetate, And extraction process repeats 2～4 times；Described water-washing process repeats 2～4 times；Described dry run is entered for using anhydrous sodium sulfate Row is dried.
  7. 5-the most according to claim 1 (4-fluorophenyl)-N (4-chlorobenzene ethyl)-7-trifluoromethyl pyrazol also [1,5-a] The synthetic method of pyrimidine-3-amide, it is characterised in that: described step 5.5) in washing process for using ethyl acetate and just own The mixed liquor of alkane washs.
CN201610349626.2A 2016-05-24 2016-05-24 Synthesis method of 5-(4-fluorophenyl)-N-(4-chlorophenylethyl)-7-trifluoromethylpyrazol[1, 5-a] pyrimidine-3-amide Pending CN105949201A (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
刘举，等: "新型3，6-二芳基吡唑并[1，5-a]嘧啶类化合物的合成", 《应用化学》 *
石磊，等: "5-(4-氯苯基)-N，N-二甲基-7-三氟甲基吡唑并[1，5-a]嘧啶-3-酰胺的合成和抗肿瘤活性测定", 《哈尔滨医科大学学报》 *

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