CN105001151B - Bu Panixi intermediates and preparation method thereof - Google Patents

Bu Panixi intermediates and preparation method thereof Download PDF

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CN105001151B
CN105001151B CN201510541078.9A CN201510541078A CN105001151B CN 105001151 B CN105001151 B CN 105001151B CN 201510541078 A CN201510541078 A CN 201510541078A CN 105001151 B CN105001151 B CN 105001151B
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trifluoromethyls
pyridin
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amino
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CN105001151A (en
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许学农
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Youbiao e-commerce (Suzhou) Co., Ltd
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Suzhou Miracpharma Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

Present invention is disclosed a kind of intermediate 3 [base of (trifluoromethyl of 6 amino 4) pyridine 3] β oxopropanoic acids ester (II) that can be used for preparing Bu Panixi (Buparlisib, I) and preparation method thereof.Its preparation process includes：3 [base of (trifluoromethyl of 6 amino 4) pyridine 3] β oxopropanoic acids esters (II) are made through nitrification, condensation and reduction reaction in the pyridine carboxylic acid of 4 trifluoromethyl 3.Present invention further teaches the method that one kind prepares Bu Panixi (I) by Formula II compound through cyclization, halo and substitution reaction.The preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, is adapted to industrialized production.

Description

Bu Panixi intermediates and preparation method thereof
Technical field
It is more particularly to a kind of the invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field It is possibly used for treatment of metastatic breast cancer medicine Bu Panixi preparation method.
Background technology
Bu Panixi (Buparlisib, also known as BMK120) is a kind of phosphorus developed by Novartis (Novartis) drugmaker The kinases of acyl inositol 3 (PIK3) inhibitor, no matter in endocrine therapy estrogen receptor positive breast cancer cell alone or in combination Strain, or all show in heterograft stronger antitumor activity.Buparlisib treatment metastatic breast cancer researchs It is in III phases clinical and confirmatory I/II phases clinical stage；Joint fulvestrant treatment postmenopausal women hormone receptor positive, The research of HER2- Locally Advanceds or joint aromatase inhibitor (AI) treatment metastatic breast cancer is in III phase clinical stages；Connection Fulvestrant treatment postmenopausal women hormone receptor positive, HER2- are closed, once received aromatase inhibitor in treatment in the past or with mTOR The research of the Locally Advanced or metastatic breast cancer treated based on inhibitor is in III phase clinical stages；Joint taxol is controlled Treat HER2-, inoperable Locally Advanced or metastatic breast cancer research and be in III phase clinical stages；Joint fulvestrant is controlled Treat the research of postmenopausal women's estrogen receptor positive metastatic breast cancer and be in I phase clinical stages.Because the medicine is still in clinic Conceptual phase, not official listing, the Chinese translation without standard, therefore its transliteration is herein " Bu Pani by the applicant West ".
Bu Panixi's is chemical entitled：5- [2,6- bis- (4- morpholinyls) -4- pyrimidine radicals] -4- (trifluoromethyl) -2- pyridines Amine, its structural formula is：
The and of international monopoly WO2007084786, WO2012109423, WO2014064058, WO 2012044727 WO2013014448 reports the synthetic method of Bu Panixi and its main intermediate, its preparation process include pyridine derivate, Pyrimidine derivatives and coupling between the two.Wherein pyridine derivate is to carry out halogen by 2- amino -4- trifluoromethyl pyridines Generation reaction or and then carry out boron esterification, and pyrimidine derivatives then with 2,4,6- trichloropyrimidines be raw material, by introducing morpholine The functional group such as base or borate, then realizes that coupling reaction prepares Bu Panixi (I).
Above-mentioned two synthetic routes A and B are analyzed, its basic ideas is to pass sequentially through Suzuki reactions i.e. suzuki reaction Realize.Obviously, the preparation of borate and suzuki reaction be required to use noble metal catalyst and borane reagent, in addition pyridine and The introducing of different functional groups on pyrimidine ring, can produce all kinds of side reactions, makes whole because its electrophilic or nucleophilic property fine difference Individual preparation process produces the shortcomings of many side reactions, high cost and complicated reaction.
For existing defective workmanship, concise in technology is developed, the economic and environment-friendly and technology of preparing that has good quality, especially Seek to can adapt to the technology of industrialized production, the economic and social benefit of the medicine, which is improved, has important reality to anticipate Justice.
The content of the invention
Be easy to get it is an object of the invention to provide a kind of raw material, concise in technology, economic and environment-friendly and suitable industrialized production Bu Panixi (Buparlisib, I) preparation method.
The present invention design and be prepared for the compound 3- as shown in Formula II [(6- amino -4- trifluoromethyls) pyridin-3-yl] - β-oxo-propionates,
Wherein R is alkyl, phenyl or the benzyl of 1-6 carbon atom.
Its preparation method comprises the following steps：With nitrating agent nitration reaction occurs for 4- trifluoromethyls-acidum nicotinicum (III) 6- nitros -4- trifluoromethyls-acidum nicotinicum (IV), the 6- nitros -4- trifluoromethyls-acidum nicotinicum (IV) and third is made Monomethyl diester occurs condensation reaction under magnesium chloride effect and 3- [(6- nitro -4- trifluoromethyls) pyridin-3-yl]-β-oxygen is made Generation-propionic ester (V), 3- [(6- nitro -4- trifluoromethyls) the pyridin-3-yl]-β-oxo-propionates (V) are sent out with reducing agent 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates (II) is made in raw reduction reaction.
The nitrating agent of the nitration reaction is nitric acid, potassium nitrate or sodium nitrate.
The catalyst of the nitration reaction is the concentrated sulfuric acid.
The temperature of the nitration reaction is 0-60 DEG C, preferably 15-25 DEG C.
The condensation reaction raw material 6- nitros -4- trifluoromethyls-acidum nicotinicum (IV) rubs with feeding intake for malonic acid monoester You are than being 1: 1-3, preferably 1: 2.0.
The condensation reaction raw material malonic acid monoester is Arrcostab, phenylester or the benzyl ester of 1-6 carbon atom, preferably first Base ester or ethyl ester, more preferably ethyl ester.
The catalyst of the condensation reaction is magnesium chloride.
The temperature of the condensation reaction is 25 to 150 DEG C, preferably 90-120 DEG C.
The solvent of the condensation reaction be 1,2- dichloroethanes, toluene, dimethyl carbonate, dioxane, dimethyl sulfoxide, N, Dinethylformamide, N, N- diethylformamides or DMA, preferably DMF.
The reducing agent of the reduction reaction is iron, zinc, tin, sodium hydrosulfite or hydrazine hydrate, preferably hydrazine hydrate.
When the reducing agent of the reduction reaction is hydrazine hydrate, addition mass percent 1-10% activated carbon and tri-chlorination Iron, can promote the progress of reaction.
The solvent of the reduction reaction is tetrahydrofuran, toluene, methanol, ethanol or isopropanol, preferred alcohol or methanol.
The temperature of the reduction reaction is 25-90 DEG C, preferably 45-75 DEG C.
Present invention also offers utilize intermediate 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionic acid The method that ester (II) prepares Bu Panixi (I),
Its preparation process includes：3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates (II) and urine Element or thiocarbamide ring-closure reaction occur under catalyst action 5- (2,6- dihydroxy -4- pyrimidine radicals) -4- (trifluoromethyl) -2- are made Pyridine amine (VI-1) or 5- (2- sulfydryl -6- hydroxyl -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VI-2)；The 5- (2,6- dihydroxy -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VI-1) or 5- (2- sulfydryl -6- hydroxyl -4- pyrimidines Base) -4- (trifluoromethyl) -2- pyridines amine (VI-2) obtained 5- (2,6- bis- halogen -4- of generation halogenating reaction under halogenating agent effect Pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VII)；5- (2,6- bis- halogen -4- the pyrimidine radicals) -4- (trifluoromethyl) - 2- pyridines amine (VII) occurs substitution reaction with morpholine and Bu Panixi (I) is made.
Wherein, ring-closure reaction raw material 3- [(6- amino -4- trifluoromethyls) the pyridin-3-yl]-β-oxo-propionates (II) it is 1: 1-3 preferably 1: 1.5-2.5, more preferably 1: 2 with the molar ratio of urea or thiocarbamide.
The catalyst of the ring-closure reaction be niter cake, potassium acid sulfate, alchlor, zinc chloride or p-methyl benzenesulfonic acid, Preferably sulfuric acid hydrogen sodium or potassium acid sulfate.
The temperature of the ring-closure reaction is 50-150 DEG C, preferably 85-125 DEG C.
The solvent of the ring-closure reaction is benzene,toluene,xylene, DMF, DMA Or dioxane, preferred toluene.
The halogenating agent of the halogenating reaction be POCl3, tribromo oxygen phosphorus, thionyl chloride, phosphorus trichloride, phosphorus tribromide or Phosphorus pentachloride, preferably POCl3 or phosphorus tribromide.
The temperature of the halogenating reaction is 50-100 DEG C, preferably 55-85 DEG C.
The solvent of the halogenating reaction be dichloromethane, 1,2- dichloromethane, ethyl acetate, acetonitrile or tetrahydrofuran, it is excellent Select dichloromethane or 1,2- dichloroethanes.
Raw material 5- (2,6- bis- halogen -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VII) of the substitution reaction Molar ratio with morpholine is 1: 2-5, preferably 1: 4.
The temperature of the substitution reaction is 40-120 DEG C, preferably 60-100 DEG C.
Methylene chloride, 1,2- dichloromethane, ethyl acetate, benzene or the toluene of the substitution reaction, preferably toluene or 1,2- dichloroethanes.
Compared to prior art, Bu Panixi (I) involved in the present invention preparation method is easy to get, technique with raw material Succinct and economic and environment-friendly the features such as, so beneficial to the industrialized production of the bulk drug, promote the development of its economic technology.
Embodiment
Technical solution of the present invention is further non-limitingly described below in conjunction with several preferred embodiments.Wherein raw material 4- trifluoromethyls-acidum nicotinicum (III) can be found in document European Journal of Organic Chemistry, (8), 1559-1568；2003 or European Journal of Organic Chemistry, (8), 1569-1575；2003 To the preparation method of identical compound.
Embodiment one：
Add at 4- trifluoromethyls-acidum nicotinicum (III) (9.6g, 0.05mol), 0-5 DEG C and be added dropwise in reaction bulb After the nitration mixture that the concentrated sulfuric acid that 10mL mass concentrations are 98% by 63% concentrated nitric acid and 30mL mass concentrations is formed, completion of dropping, Reaction 6-8 hours is stirred at room temperature, TLC detection reactions are completed.Reaction solution is poured onto in frozen water, extracted with ethyl acetate, matter is used Concentration is measured to wash for 10% NaOH.Dry, decompression removes solvent, obtains light yellow liquid grease 6- nitro -4- trifluoros Methyl-acidum nicotinicum (IV) 10.6g, yield 89.8%；EI-MS m/z：237[M+H]+。
Embodiment two：
6- nitros -4- trifluoromethyls-acidum nicotinicum (IV) (5.9g, 25mmol), the miaow of carbonyl two are added in reaction bulb Azoles (4.1g, 27.5mmol) and DMF 100mL, are stirred at room temperature 3 hours, addition monoethyl malonate (6.6g, 50mmol) with magnesium chloride (3.1g, 32.5mmol), 100-110 DEG C is warming up to, continues to react 10-12 hours, TLC detection reactions Terminate.Room temperature is down to, reaction solution is poured into 250mL frozen water, is stirred 40 minutes, is filtered, dries, obtains yellow solid 3- [(6- nitro -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates (V) 6.2g, yield 81.0%；EI-MS m/z：307 [M+H]+。
Embodiment three：
In reaction bulb add 3- [(6- nitro -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates (V) (3.1g, 10mmol), ferric trichloride (0.27g, 1mmol), activated carbon 0.4g and ethanol 50mL, it is 80% water that mass concentration is added dropwise at room temperature Hydrazine (1.25g, 20mmol) is closed, after finishing, 50-60 DEG C is warming up to, reacts 4-5 hours, filtering, concentration removes ethanol, residue With recrystallisation from isopropanol, filter, dry, obtain off-white powder 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxygen Generation-propionic ester (II) 2.3g, yield 83.3%；1H NMR(DMSO-d6) δ 1.15 (t, 3H), 3.98 (q, 2H), 4.33 (br s, 2H), 5.23 (s, 2H), 6.05 (s, 1H), 6.88 (s, 1H)；EI-MS m/z：277[M+H]+。
Example IV：
3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxygen is added in the reaction bulb with reflux water-dividing device Generation-propionic ester (II) (2.8g, 10mmol), urea (1.2g, 20mmol), niter cake (0.36g, 3mmol) and toluene 50mL, Backflow is to slowly warm up to, 3-5 hours are maintained the reflux for, it is anhydrous into water knockout drum to ooze now.Solvent is recovered under reduced pressure, adds into residue Enter the sodium hydroxide solution that mass concentration is 10%, be warming up to 90-95 DEG C, stirring reaction 3-4 hours is down to room temperature, uses quality The salt acid for adjusting pH that concentration is 10% to 3-4, ice-water bath cooling has solid precipitation, filtered, and vacuum drying obtains off-white powder 5- (2,6- dihydroxy -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VI-1) 2.2g, yield 80.9%, EI-MS m/z： 273[M+H]+。
Embodiment five：
3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxygen is added in the reaction bulb with reflux water-dividing device Generation-propionic ester (II) (2.8g, 10mmol), thiocarbamide (1.5g, 20mmol), potassium acid sulfate (0.41g, 3mmol) and toluene 50mL, Backflow is to slowly warm up to, 2-4 hours are maintained the reflux for, it is anhydrous into water knockout drum to ooze now.Solvent is recovered under reduced pressure, adds into residue Enter the sodium hydroxide solution that mass concentration is 10%, be warming up to 90-95 DEG C, stirring reaction 3-4 hours is down to room temperature, uses quality The salt acid for adjusting pH that concentration is 10% to 3-4, ice-water bath cooling has solid precipitation, filtered, and vacuum drying obtains faint yellow solid 5- (2- sulfydryl -6- hydroxyl -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VI-2) 2.5g, yield 86.8%, EI-MS m/z：289[M+H]+。
Embodiment six：
Under blanket of nitrogen, 5- (2,6- dihydroxy -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridine amine is added in reaction bulb (VI-1) (2.7g, 10mmol), phosphorus tribromide (6.8g, 25mmol) and 1,2- dichloroethanes 50mL, are warming up to 70-80 DEG C, stir Reaction 4-6 hours is mixed, TLC detection reactions are completed.Cooling, mass concentration is added into reaction system molten for 10% NaOH Liquid, separates aqueous phase, organic phase water and saturated common salt water washing, anhydrous sodium sulfate drying.Solvent is recovered under reduced pressure, brown oil is obtained Thing 5- (2,6- bis- bromo- 4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine (VII) 3.1g, yield 78.5%, EI-MS m/z： 396[M+H]+。
Embodiment seven：
Under blanket of nitrogen, 5- (2- sulfydryl -6- hydroxyl -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines are added in reaction bulb Amine (VI-2) (2.9g, 10mmol) and POCl3 (15.3g, 100mmol), are warming up to 100-110 DEG C, stirring reaction 3-5 is small When, TLC detection reactions are completed.Vacuum distillation goes out excessive POCl3, and residue is down to room temperature, and ice is added into reaction system Water, is kept for 0-5 DEG C stir 30 minutes, is extracted 3 times with dichloromethane, merge organic phase, successively with water and saturated common salt water washing, Anhydrous sodium sulfate drying.Solvent is recovered under reduced pressure, obtain yellow chlorine color grease 5- (2,6- bis- chloro- 4- pyrimidine radicals) -4- (trifluoromethyl) - 2- pyridines amine (VII) 2.6g, yield 84.7%, EI-MS m/z：308[M+H]+。
Embodiment eight：
Under blanket of nitrogen, 5- (2,6- bis- bromo- 4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridine amine is added in reaction bulb (VII) (2.0g, 5mmol), morpholine (1.74g, 20mmol), 1,2- dichloroethanes 50mL and water 25mL, are warming up to 70-80 DEG C, Stirring reaction 3-5 hours, TLC detection reactions are completed.Room temperature, stratification are down to, aqueous phase uses 1,2- dichloroethanes to be extracted twice, Merge organic phase and be transferred in reaction bulb, the hydrochloric acid 50mL that mass concentration is 10% is added dropwise, be warming up to 40-45 DEG C, stirring is anti- Answer 10-12 hours.Stand, separate aqueous phase, organic phase is washed twice with water, it is 10% to merge and used under aqueous phase, ice bath mass concentration Sodium hydroxide solution adjust pH to 7-8, have solid precipitation, filter, filter cake washs with cold n-butanol, vacuum drying obtains palm fibre Brown solid Bu Panixi (I) 1.8g, yield 87.8%.1H NMR(CDCl3) δ 3.60 (m, 4H), 3.76 (m, 12H), 4.78 (brs, 2H), 5.96 (s, 1H), 6.77 (s, 1H)；EI-MS m/z：411[M+H]+,
Embodiment nine：
Under blanket of nitrogen, 5- (2,6- bis- chloro- 4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridine amine is added in reaction bulb (VII) (1.5g, 5mmol), morpholine (1.74g, 20mmol), toluene 50mL and water 25mL, are warming up to 80-90 DEG C, stirring reaction 4-6 hours, TLC detection reactions were completed.Room temperature is down to, stratification, aqueous phase is extracted twice with toluene, merges organic phase and shift Into reaction bulb, the hydrochloric acid 50mL that mass concentration is 10% is added dropwise, 40-45 DEG C, stirring reaction 10-12 hours is warming up to.Stand, Aqueous phase is separated, organic phase is washed twice with water, merge and adjusted under aqueous phase, ice bath with mass concentration for 10% sodium hydroxide solution PH has solid precipitation to 7-8, and filtering, filter cake is washed with cold isopropanol, is dried in vacuo, obtains sepia solid Bu Panixi (I) 1.7g, yield 82.9%；1H NMR(CDCl3) δ 3.60 (m, 4H), 3.76 (m, 12H), 4.78 (brs, 2H), 5.96 (s, 1H), 6.77 (s, 1H)；EI-MS m/z：411[M+H]+。
It is pointed out that the technical concept and feature of above-described embodiment only to illustrate the invention, ripe its object is to allow Present disclosure can be understood and implement according to this by knowing the personage of technique, and the protection model of the present invention can not be limited with this Enclose.Any equivalent change or modification in accordance with the spirit of the invention, should all be included within the scope of the present invention.

Claims (10)

1. a kind of compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates as shown in Formula II, its Middle R is alkyl, phenyl or the benzyl of 1-6 carbon atom,
2. a kind of compound 3- as claimed in claim 1 [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates Preparation method, it is characterised in that it comprises the following steps：With nitrating agent nitration reaction occurs for 4- trifluoromethyls-acidum nicotinicum 6- nitros -4- trifluoromethyls-acidum nicotinicum, the 6- nitros -4- trifluoromethyls-acidum nicotinicum and malonic acid monoester is made Occur condensation reaction under magnesium chloride effect and 3- [(6- nitro -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates be made, 3- [(6- nitro -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates occur reduction reaction with reducing agent and 3- are made [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates.
3. the system of compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates as claimed in claim 2 Preparation Method, it is characterised in that the nitrating agent of the nitration reaction is nitric acid, potassium nitrate or sodium nitrate.
4. the system of compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates as claimed in claim 2 Preparation Method, it is characterised in that the throwing of the condensation reaction raw material 6- nitros -4- trifluoromethyls-acidum nicotinicum and malonic acid monoester It is 1 to expect mol ratio:1-3, the condensation reaction raw material malonic acid monoester is Arrcostab, phenylester or the benzyl of 1-6 carbon atom Ester.
5. the system of compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates as claimed in claim 2 Preparation Method, it is characterised in that the temperature of the condensation reaction is 25 to 150 DEG C, and solvent is 1,2- dichloroethanes, toluene, carbonic acid two Methyl esters, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N, N- diethylformamides or DMAC N,N' dimethyl acetamide.
6. the system of compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates as claimed in claim 2 Preparation Method, it is characterised in that the reducing agent of the reduction reaction is iron, zinc, tin, sodium hydrosulfite or hydrazine hydrate.
7. one kind utilizes Formula II compound 3- as claimed in claim 1 [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxygen The method that generation-propionic ester prepares Bu Panixi, it is characterised in that Formula II compound is issued with urea or thiocarbamide in catalyst action 5- (2,6- dihydroxy -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine or 5- (2- sulfydryl -6- hydroxyls is made in raw ring-closure reaction Base -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridine amine；5- (2,6- dihydroxy -4- the pyrimidine radicals) -4- (trifluoromethyl) - 2- pyridines amine or 5- (2- sulfydryl -6- hydroxyl -4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine occur under halogenating agent effect 5- (halogen -4- pyrimidine radicals of 2,6- bis-) -4- (trifluoromethyl) -2- pyridine amine is made in halogenating reaction；The 5- (halogens of 2,6- bis-- 4- pyrimidine radicals) -4- (trifluoromethyl) -2- pyridines amine and morpholine occur substitution reaction and Bu Panixi (I) be made,
8. compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates is utilized as claimed in claim 7 The method for preparing Bu Panixi, it is characterised in that the catalyst of the ring-closure reaction is niter cake, potassium acid sulfate, tri-chlorination Aluminium, zinc chloride or p-methyl benzenesulfonic acid.
9. compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionates is utilized as claimed in claim 7 The method for preparing Bu Panixi, it is characterised in that the halogenating agent of the halogenating reaction is POCl3, tribromo oxygen phosphorus, dichloro Asia Sulfone, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride.
10. compound 3- [(6- amino -4- trifluoromethyls) pyridin-3-yl]-β-oxo-propionic acid is utilized as claimed in claim 7 The method that ester prepares Bu Panixi, it is characterised in that raw material 5- (2,6- bis- halogen -4- pyrimidine radicals) -4- of the substitution reaction The molar ratio of (trifluoromethyl) -2- pyridines amine and morpholine is 1:2-5.
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