CN104650045A - Preparation method of avanafil - Google Patents

Preparation method of avanafil Download PDF

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CN104650045A
CN104650045A CN201410653978.8A CN201410653978A CN104650045A CN 104650045 A CN104650045 A CN 104650045A CN 201410653978 A CN201410653978 A CN 201410653978A CN 104650045 A CN104650045 A CN 104650045A
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reaction
solvent
acid
sodium
hydroxide
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CN104650045B (en
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田广辉
李军奇
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Suzhou Wangshan Wangshui Biopharmaceutical Co ltd
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Suzhou Vigonvita Life Sciences Co ltd
Topharman Shanghai Co Ltd
Topharman Shandong Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Abstract

The invention relates to a preparation method of avanafil and a new compound provided in a preparation process. According to the method, 5-uracil carboxylic acid or an ester thereof is taken as the raw material, and the avanafil meeting the clinical requirements can be synthesized at a relatively cost; besides, the preparation method is simple and convenient to operate, mild in reaction conditions, high in yield, low in cost, environmentally friendly and suitable for industrial large-scale production of the avanafil.

Description

The preparation method of avanaphil
Technical field
The invention belongs to medicinal chemistry art, in particular to the preparation method of avanaphil (avanafil) (it is a kind of PDE5 inhibitor, i.e. 5 type phosphodiesterase inhibitors), also relate to the new compound provided in preparation process.
Background technology
Avanaphil (avanafil) is highly selective phosphodiesterase-5 (PDE-5) inhibitor being used for the treatment of male erectile dysfunction (ED) of authorizing Vivus company of the U.S. to develop by Japanese Tanabe Mitsubishi Pharmaceutical Co, in Nikkei U.S. FDA approval April 27 in 2012 in U.S.'s listing, commodity are called Stendra.This medical instrument has the mechanism of action identical with other PDE-5 inhibitor, but there is unique pharmacokinetics and pharmacodynamic profiles, it is advantageous that oral absorption is faster, many ED patients can live by successful Progressive symmetric erythrokeratodermia in 0.5 hour after use this product, equivalence or other PDE-5 inhibitor be better than in the market, as Virga (trade(brand)name: vigour), Vardenafil (trade(brand)name: Ai Lida), Tadalafei (trade(brand)name: Tadalafil) etc., onset time after vigour and Ai Lida take is about 30 minutes, Tadalafil is 2 hours, therefore, the quick-acting advantages of avanaphil can make it more by the favor of ED patient.The highly selective of avanaphil then causes its side effect less compared with other like products, and the incidences such as its backache and audiovisual obstacle are lower.
To be 3-chloro-4-methoxy benzylamine (II) there is nucleophilic substitution reaction with the chloro-2-methylthiopyrimidine of 4--5-carboxylic acid, ethyl ester (III) to avanaphil synthetic route disclosed in international patent application WO2001019802A1 obtains 4-(3-chloro-4-methoxy benzamido group)-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (IV), then compound IV metachloroperbenzoic acid (mCPBA) oxidation is obtained 4-(3-chloro-4-methoxy benzamido group)-2-methanesulfonyl pyrimidine-5-carboxylic acid, ethyl ester (V), be there is substitution reaction in compound V and L-dried meat ammonia alcohol i.e. (S)-2-hydroxymethyl pyrrolidine (VI) and obtain compound VI I, after compound VI I hydrolysis and 2-pyrimidine ethamine (IX) carry out amidate action and obtain avanaphil, synthetic route is as shown in reaction formula 1:
reaction formula 1:
In this route; the price comparison of the chloro-2-methylthiopyrimidine of raw material 4--5-carboxylic acid, ethyl ester (III) is expensive; easily produce the impurity that difficulty is removed when being oxidized 4-(3-chloro-4-methoxy benzamido group)-2-methylthiopyrimidine-5-carboxylic acid, ethyl ester (IV) with metachloroperbenzoic acid (mCPBA), and 4-(3-chloro-4-methoxy benzamido group)-2-methanesulfonyl pyrimidine-5-carboxylic acid, ethyl ester (V) is too low with the reaction yield of L-dried meat ammonia alcohol (VI).
Due to above-mentioned preparation method, to there is cost high, and yield is low, the many and shortcoming such as not easily separated of impurity, be therefore necessary that searching one is economic, practical, environmental protection, stable, reasonable variation route, to improve technology stability, reduce costs, improve the quality of products.
Summary of the invention
For above-mentioned weak point, an object of the present invention is to provide a kind of method preparing avanaphil newly, the method utilizes raw material cheap and easy to get and reagent, the avanaphil meeting clinical demand can be synthesized at lower cost, and easy and simple to handle, reaction conditions is gentle, yield is high, cost is low, environmentally friendly, be applicable to industrialization scale operation avanaphil.
Another object of the present invention is to provide the new compound related in above-mentioned preparation method.
To achieve these goals, the method that to the invention provides with 5-uridylic carboxylic acid or its ester be Material synthesis avanaphil, described preparation method is one of following method:
Method one:
5-uridylic carboxylicesters (X) generates 2,4-dihalo-5-pyrimidine carboxylic ester (XI) through halogenating reaction;
Compounds X I and 3-chloro-4-methoxy benzylamine (II) or its salt generation substitution reaction, generate 2-halo-4-(3-chloro-4-methoxy benzamido group)-5-pyrimidine carboxylic ester (XII), it can carry out separation and purification, also can not be separated and be directly used in next step;
Compounds X II and L-dried meat ammonia alcohol (VI) carry out replacing further generating compound VI I,
Compound VI I and 2-pyrimidine ethamine (IX) or its salt generation ammonolysis reaction obtain avanaphil (I); Or,
Compound VI I is first hydrolyzed and obtains acid (VIII), then carries out amidate action with 2-pyrimidine ethamine (IX) or its salt and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 2:
reaction formula 2:
Wherein,
R is selected from the straight or branched alkyl of C1 ~ C6, the straight or branched alkyl of preferred C1 ~ C4, most preferable, ethyl or the tertiary butyl;
X is selected from halogen, is preferably chlorine or bromine;
Method two
5-uridylic carboxylic acid (XIII) and 2-pyrimidine ethamine (IX) or its salt carry out amidate action or 5-uridylic carboxylicesters (X) and carry out ammonolysis reaction with 2-pyrimidine ethamine (IX) or its salt and obtain compounds X IV;
Compounds X IV obtains halides XV through halogenating reaction;
Halides XV and 3-chloro-4-methoxy benzylamine (II) or its salt generation substitution reaction generate compounds X VI;
Compounds X VI and L-dried meat ammonia alcohol (VI) carry out substitution reaction and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 3:
reaction formula 3:
Wherein,
R is selected from the straight or branched alkyl of C1 ~ C6, the straight or branched alkyl of preferred C1 ~ C4, most preferable, ethyl or the tertiary butyl;
X is selected from halogen, is preferably chlorine or bromine;
Method three:
5-uridylic carboxylic acid (XIII) is through halo and carboxylic acid activated reacting generating compound XVII;
Compounds X VII and 2-pyrimidine ethamine (IX) or its salt carry out ammonolysis reaction and generate compounds X V;
Compounds X V replaces further with 3-chloro-4-methoxy benzylamine (II) or its salt and generates compounds X VI;
Compounds X VI and L-dried meat ammonia alcohol (VI) carry out substitution reaction and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 4:
reaction formula 4:
Wherein, X is selected from halogen, is preferably chlorine or bromine.
In the above-mentioned methods, described substitution reaction can be carried out in the presence of a base, and wherein, described alkali can be selected from mineral alkali, organic bases and its combination.Such as, inorganic basis is as being selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrated barta, calcium hydroxide, cesium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, Strontium carbonate powder, cesium carbonate, sodium sulphite, sodium hydrogen etc. and its combination; Organic bases is as being selected from sodium alkoxide, potassium alcoholate, butyllithium, 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, quinoline, DMAP (DMAP), triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine etc. and its combination.Wherein, sodium alkoxide such as can be selected from sodium methylate, sodium ethylate, sodium propylate, sodium isopropylate, propyl carbinol sodium, sodium tert-butoxide etc. and its combination; Potassium alcoholate such as can be selected from potassium methylate, potassium ethylate, potassium propylate, potassium isopropoxide, propyl carbinol potassium, potassium tert.-butoxide etc. and its combination.Described alkali is preferably selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, potassium tert.-butoxide, pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine and its combination.The reaction solvent of described substitution reaction can be selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent and other solvents.Wherein, described aromatic hydrocarbon solvent such as can be selected from benzene,toluene,xylene, chlorobenzene, oil of mirbane etc. and its combination; Described ether solvent such as can be selected from tetrahydrofuran (THF) (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane etc. and its combination; Described halogenated hydrocarbon solvent such as can be selected from methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc. and its combination; Other solvents described such as can be selected from N, dinethylformamide (DMF), N,N-dimethylacetamide, methyl-sulphoxide (DMSO), N-Methyl pyrrolidone, hexamethylphosphoramide, acetone, acetonitrile, ethyl acetate etc. and its combination.But the present invention is not limited to above-mentioned solvent.The temperature of reaction of described substitution reaction is not particularly limited, preferably the temperature range of-30 DEG C ~ 300 DEG C, more preferably-10 DEG C ~ 150 DEG C.The reaction times of described substitution reaction is not particularly limited, preferably 1 ~ 12 hour.
In the above-mentioned methods, described hydrolysis reaction can carry out in presence of an acid.Described acid can be selected from organic acid, mineral acid or its combination, such as being selected from one or more in sulfuric acid, hydrochloric acid, hydrogen chloride gas, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, formic acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, perchloric acid etc., but be not limited to above-mentioned acid.Described hydrolysis reaction also can carry out in the presence of a base.Described alkali can be selected from mineral alkali, organic bases and its combination.Described inorganic basis is as being selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrated barta, calcium hydroxide, cesium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, Strontium carbonate powder, cesium carbonate and its combination.Described organic bases is as being selected from Potassium ethanoate, sodium-acetate, 1,8-diazacyclo [5,4,0] hendecene-7 (DBU), pyridine, quinoline, DMAP (DMAP), triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine etc. and its combination.Preferred described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate and its combination.Described hydrolysis reaction can carry out in suitable solvent.Described solvent can for being selected from water, C 1~ C 5alcohol (such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, ethylene glycol, propylene glycol, glycerol etc. or its combination), N, dinethylformamide (DMF), N, N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide (DMSO), tetrahydrofuran (THF) (THF), acetonitrile, dioxane, morpholine, N-Methyl pyrrolidone, methylene dichloride, chloroform, glycol dimethyl ether, diethylene glycol dimethyl ether, one or more in ethylene glycol monomethyl ether etc., preferably water, methyl alcohol, ethanol, tetrahydrofuran (THF) (THF), one or more in dioxane.The temperature of reaction of described hydrolysis reaction is not particularly limited, but preferably at-10 DEG C ~ 300 DEG C, between more preferably 0 DEG C ~ 100 DEG C.The reaction times of described hydrolysis reaction is not particularly limited, but preferably at 10 minutes ~ 24 hours, more preferably between 0.5 ~ 10 hour.
In the above-mentioned methods, described halogenating reaction carries out under halogenating agent exists.Described halogenating agent can for being selected from one or more in phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, chlorine, bromine, iodine and tribromo oxygen phosphorus.Described halogenating reaction can have or carry out under the existence of reactionless solvent, described reaction solvent is not particularly limited, as long as it is disturbance reponse not, such as can for being selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide etc.The temperature of reaction of described halogenating reaction is not particularly limited, but preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 150 DEG C.
In the above-mentioned methods, described halo and carboxylic acid activated reaction are carried out under halogenating agent exists.Described halogenating agent can for being selected from one or more in sulfur oxychloride, thionyl bromide, pivaloyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride or tribromo oxygen phosphorus.Described halo and carboxylic acid activated reaction can have or carry out under the existence of reactionless solvent, described reaction solvent is not particularly limited, as long as it is disturbance reponse not, such as can for being selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide etc.The temperature of reaction of described halo and carboxylic acid activated reaction is not particularly limited, but preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 150 DEG C.
In the above-mentioned methods, described ammonolysis reaction in the presence of a base, carries out in suitable solvent.Described alkali can for being selected from pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, quinoline, DMAP (DMAP), triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, sodium methylate, sodium ethylate, potassium tert.-butoxide, butyllithium, 1, 8-diazacyclo [5, 4, 0] hendecene-7 (DBU), N-methylmorpholine, quinoline, DMAP (DMAP), sodium hydrogen, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, saleratus, one or more in sodium carbonate and salt of wormwood.The reaction solvent of described ammonolysis reaction can be selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, other solvents and its combination.Wherein, described aromatic hydrocarbon solvent such as can for being selected from one or more in benzene,toluene,xylene etc.; Described ether solvent such as can for being selected from one or more in tetrahydrofuran (THF) (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane etc.; Described halogenated hydrocarbon solvent such as can for being selected from one or more in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride etc.; Other solvents described such as can for being selected from methyl alcohol, ethanol, ethylene glycol, normal hexane, hexanaphthene, N, dinethylformamide (DMF), N, one or more in N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide (DMSO), N-Methyl pyrrolidone, acetone, acetonitrile, ethyl acetate etc., but the present invention is not limited to above-mentioned solvent.The temperature of reaction of described ammonolysis reaction is not particularly limited, but preferably at-30 DEG C ~ 150 DEG C, between more preferably-10 DEG C ~ 120 DEG C.The reaction times of described ammonolysis reaction is not particularly limited, but preferably between 10 minutes ~ 24 hours.
In the above-mentioned methods, described amidate action can adopt two kinds of methods to carry out.The first amidation method is having or under catalyst-free existence, reacting and generate carboxylic acid halides, then carry out ammonolysis reaction with amine with halogenating agent.Described halogenating agent can for being selected from one or more in sulfur oxychloride, oxalyl chloride, thionyl bromide, phosphorus oxychloride, tribromo oxygen phosphorus, phosphorus trichloride, phosphorus pentachloride, pivaloyl chloride etc.Described catalyzer can for being selected from one or more in DMF (DMF), Diethyl Aniline, xylidine etc.The reaction of described generation carboxylic acid halides can have or carry out under the existence of reactionless solvent, described reaction solvent is not particularly limited, as long as it is disturbance reponse not, such as can for being selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide etc.The temperature of reaction of the reaction of described generation carboxylic acid halides is not particularly limited, but preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 100 DEG C.The condition of described ammonolysis reaction is described above.
The second amidation method uses condensing agent, having or under catalyst-free condition, carrying out in the presence of a base.Described condensing agent can for being selected from N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDCl), phosphinylidyne diimidazole (CDI), N, N'-DIC (DIC), O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HBTU), one or more in benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).Described catalyzer can for being selected from one or more in 1-hydroxyl-benzotriazole (HOBt), 4-dimethylamino pyridine (DMAP) etc.Described alkali can for being selected from triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, Trimethylamine 99, pyridine, 2,6-lutidine, DMAP, piperidines, tetramethyleneimine, quinoline, morpholine, N-methylmorpholine, N-ethylmorpholine, diisopropylamine, diisopropylethylamine, 1,8-diazacyclo [5,4,0] one or more in hendecene-7 (DBU) or 1,5-diazabicylo [4.3.0]--5-alkene in ninth of the ten Heavenly Stems (DBN) etc.The reaction solvent of described the second amidation method can for being selected from: hydro carbons, as benzene, dimethylbenzene, toluene, methylene dichloride or chloroform; Ethers, as tetrahydrofuran (THF), ether, propyl ether or Isosorbide-5-Nitrae-dioxane; Amides, as DMF, N, N-diethylformamide or N,N-dimethylacetamide; Nitrile, as acetonitrile; Other, as methyl-sulphoxide etc.; And the mixture of above-mentioned solvent, wherein, preferred reaction solvent is tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, N,N-dimethylacetamide or methyl-sulphoxide.The temperature of reaction of described the second amidation method is not particularly limited, only otherwise affect reaction carries out, but preferred at-20 DEG C ~ 200 DEG C, between more preferably-0 DEG C ~ 100 DEG C.
Another aspect of the present invention is to provide following intermediate:
Wherein, X is selected from halogen independently of one another, is preferably chlorine or bromine independently of one another.
Three routes of the present invention all have passed through 2 step substitution reactions, make use of 4 halogens on pyrimidine ring more active than 2 halogens, so reaction sequence is all 4 elder generations of two halides and the chloro-4-emilium tosylate of 3-or its reactant salt, then be that 2 of pyrimidine and L-dried meat ammonia alcohol react.
The invention has the advantages that and adopt raw material cheap and easy to get and reagent, easy operation, gentle reaction conditions produces high-quality avanaphil, and this operational path can be used for the large production of mass-producing.
Embodiment
Illustrate the present invention so that those skilled in the art more easily understand the present invention below with reference to embodiment, but the present invention is not limited to the following example.
Embodiment
The preparation of the chloro-5-pyrimidinecarboxylicacidethylester of embodiment 12,4-bis-
To in 100ml there-necked flask, add uridylic-5-carboxylic acid, ethyl ester (2.2g, 11.95mmol), DMA (2g, 16.50mmol).Add phosphorus oxychloride (9.2g, 60mmol) gradually under ice bath, and constantly stir.Dropwise rear stirring 10min, heat up 110 DEG C gradually, and be incubated 3h reaction.Reaction solution is slowly poured into cancellation in mixture of ice and water (100ml), and constantly stirs, maintain the temperature at less than 5 DEG C.By ethyl acetate (200ml) extracting twice.Organic phase merges, and with saturated brine washing, dry concentrating obtains crude product.Crude product obtains solid 1.8g through column chromatography, yield 68%.
1H NMR(DMSO-d 6,400MHz):δ9.13(s,1H),4.37(q,2H),1.32(t,3H)。
The preparation of the chloro-5-pyrimidine carboxylic tert-butyl ester of embodiment 22,4-bis-
To in 100ml there-necked flask, add uridylic-5-carboxylic acid tert-butyl ester (2.5g, 11.95mmol), DMA (2g, 16.50mmol).Add phosphorus oxychloride (9.2g, 60mmol) gradually under ice bath, and constantly stir.Dropwise rear stirring 10min, heat up 110 DEG C gradually, and be incubated 3h reaction.Be concentrated into dry, add saturated sodium bicarbonate solution (100ml), maintain the temperature at less than 5 DEG C.By ethyl acetate (200ml) extracting twice.Organic phase merges, and with saturated brine washing, dry concentrating obtains crude product.Crude product obtains solid 1.9g through column chromatography, yield 65%.
1H NMR(DMSO-d 6,400MHz):δ9.13(s,1H),1.43(s,9H)。MS(m/z)：250(MH +)。
The preparation of embodiment 3 4-(3-chloro-4-methoxy benzamido group)-2-[(S)-2-hydroxymethylpyrrol alkyl-1-]-5-pyrimidinecarboxylicacidethylester
To in 25ml there-necked flask, add the chloro-5-pyrimidinecarboxylicacidethylester (150mg, 0.679mmol) of 2,4-bis-successively, triethylamine (270mg, 2.668mmol), methylene dichloride (2ml), is stirred to dissolving gradually, ice bath is cooled to less than 0 DEG C, the chloro-4-methoxybenzylamine hydrochloride (145mg, 0.697mmol) of the 3-in batches added in reaction solution, thermal reacting for two hours after reinforced.In reaction solution, dropwise add L-dried meat ammonia alcohol (105mg, 1.038mmol) again, finish, continue stirring reaction 2 hours.Reaction solution is joined water (30ml), use dichloromethane extraction.Merge organic phase, washing twice, anhydrous sodium sulfate drying, filtering siccative, concentrated organic phase obtains crude product.Crude product obtains product 200mg through silica gel column chromatography (sherwood oil: ethyl acetate=6:1), yield 70%. 1H NMR(DMSO-d 6,400Hz):δ8.58(s,1H),8.42(d,1H),7.36(s,1H),7.19(d,1H),6.86(d,1H),4.59(s,2H),4.28(m,3H),3.88(s,3H),3.45(m,5H),1.85(m,4H),1.33(t,3H)。MS(m/z)：421(MH +)。
The preparation of embodiment 4 4-(3-chloro-4-methoxy benzamido group)-2-[(S)-2-hydroxymethylpyrrol alkyl-1-]-5-pyrimidine carboxylic tert-butyl ester
To in 25ml there-necked flask, add 2, the 4-bis-chloro-5-pyrimidine carboxylic tert-butyl ester (169mg, 0.679mmol) successively, triethylamine (270mg, 2.668mmol), methylene dichloride (2ml), is stirred to dissolving gradually, ice bath is cooled to less than 0 DEG C, the chloro-4-methoxybenzylamine hydrochloride (145mg, 0.697mmol) of the 3-in batches added in reaction solution, thermal reacting for two hours after reinforced.In reaction solution, dropwise add L-dried meat ammonia alcohol (105mg, 1.038mmol) again, finish, continue stirring reaction 2 hours.Reaction solution is joined water (30ml), use dichloromethane extraction.Merge organic phase, washing twice, anhydrous sodium sulfate drying, filtering siccative, concentrated organic phase obtains crude product.Crude product obtains product 228mg through silica gel column chromatography, yield 75%.
1HNMR(DMSO-d 6,400Hz):δ8.60(s,1H),8.40(d,1H),7.40(s,1H),7.20(d,1H),6.90(d,1H),4.53(s,2H),4.05(d,1H),3.80(s,3H),3.45(m,5H),1.64(m,4H),1.43(d,9H)。MS(m/z)：449(MH +)。
The preparation of embodiment 5 4-(3-chloro-4-methoxy benzamido group)-2-[(S)-2-hydroxymethylpyrrol alkyl-1-]-5-pyrimidine carboxylic
To in 250ml there-necked flask, add the product (3.4g, 8.095mmol) of embodiment 3 successively, methyl-sulphoxide (34ml), be stirred to dissolving under ice bath cooling, then in reaction solution, drip the 10%NaOH aqueous solution (23ml) gradually.After dripping, rise to room temperature, stirring is spent the night.Drip 10% acetic acid solution in ice bath downhill reaction liquid, about adjusting pH to 6 ~ 7, stir 0.5h and separate out white solid.Filter, tetrahydrofuran (THF) is pulled an oar, and suction filtration obtains white solid, dries to obtain target compound 2.23g, yield 70%.
1HNMR(DMSO-d 6,400Hz):δ8.67(s,1H),8.44(d,1H),7.42(d,1H),7.30(d,1H),7.09(d,1H),4.55(s,2H),4.09(d,1H),3.82(s,3H),3.48(m,5H),1.91(ddd,4H)。MS(m/z)：393(MH +)。
The preparation of embodiment 6 4-(3-chloro-4-methoxy benzamido group)-2-[(S)-2-hydroxymethylpyrrol alkyl-1-]-5-pyrimidine carboxylic
The product (5.0g, 11.14mmol) of embodiment 4 is added, methylene dichloride/trifluoroacetic acid (30ml, V/V=1:1), stirred overnight at room temperature in 100mL eggplant-shape bottle.Concentration of reaction solution, about slowly dripping saturated sodium bicarbonate aqueous solution tune pH to 6 ~ 7, stirs 0.5h and separates out white solid.Filter, tetrahydrofuran (THF) is pulled an oar, and suction filtration obtains white solid, dries to obtain target compound (3.8g, 87%).
1HNMR(DMSO-d 6,400Hz):δ8.67(s,1H),8.44(d,1H),7.42(d,1H),7.30(d,1H),7.09(d,1H),4.55(s,2H),4.09(d,1H),3.82(s,3H),3.48(m,5H),1.91(ddd,4H)。MS(m/z)：393(MH +)。
The preparation of embodiment 7 avanaphil
In 50ml there-necked flask, drop into 2-amino methylpyrimidine acetate (0.65g, 3.846mmol), triethylamine (0.36g, 3.558mmol) and DMF (10ml), stir 0.5h.In reaction solution, add the product (1.00g, 2.550mmol) of embodiment 5, EDCI (0.54g, 2.817mmol) and I-hydroxybenzotriazole (0.38g, 2.812mmol) more successively, stirring at room temperature reacts 8 hours.Reaction solution is poured in sodium hydrogen carbonate solution, and is extracted with ethyl acetate.Merge organic phase, saturated common salt is washed, and anhydrous sodium sulfate drying, filtering siccative, concentrated organic phase obtains crude product.Crude product recrystallization obtains avanaphil 0.74g, yield 60%.
1HNMR(DMSO-d 6,400Hz):δ9.15(s,1H),8.75(d,2H),8.54(s,1H),7.32(m,1H),7.07(d,1H),4.57(s,2H),4.50(s,2H),4.11(s,1H),3.82(s,3H),3.51(m,5H),1.90(ddd,4H)。MS(m/z)：483(MH +)。
The preparation of embodiment 8 avanaphil
Under room temperature condition, in 50ml there-necked flask, add the product (1.2g, 3.1mmol) of embodiment 5 successively, sulfur oxychloride (10ml), be heated to 80 DEG C of reactions 4 hours.Be evaporated to dry 4-(3-chloro-4-methoxy benzamido group)-2-[(S)-2-hydroxymethylpyrrol alkyl-1-]-5-pyrimidine formyl chloride, solid 1.2g, yield 95%.
In 50ml there-necked flask, add 2-amino methylpyrimidine (318mg, 2.92mmol), triethylamine (1.2ml, 8.43mmol), methylene dichloride (8ml), slowly drips upper step reaction gained crude product (1.2g under condition of ice bath, methylene dichloride (5ml) solution 2.92mmol), adds stirred overnight at room temperature.Add methylene dichloride, water extracts 2 times, after merging organic phase, wash 2 times with water, anhydrous sodium sulfate drying, concentratedly obtain crude product.Crude product obtains white solid 0.9g through column chromatography, i.e. avanaphil, yield 64%.
1HNMR(DMSO-d 6,400Hz):δ9.15(s,1H),8.75(d,2H),8.54(s,1H),7.32(m,1H),7.07(d,1H),4.57(s,2H),4.50(s,2H),4.11(s,1H),3.82(s,3H),3.51(m,5H),1.90(ddd,4H)。MS(m/z)：483(MH +)。
The preparation of embodiment 9 avanaphil
By the product (2.0g, 4.75mmol) of embodiment 3,2-amino methylpyrimidine (537mg, 4.75mmol), is dissolved in methylene dichloride (20ml), stirred overnight at room temperature.Add methylene dichloride, water extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate to obtain crude product, obtain white solid 1.0g through purification by silica gel column chromatography, i.e. avanaphil, yield 44%.
1HNMR(DMSO-d 6,400Hz):δ9.15(s,1H),8.75(d,2H),8.54(s,1H),7.32(m,1H),7.07(d,1H),4.57(s,2H),4.50(s,2H),4.11(s,1H),3.82(s,3H),3.51(m,5H),1.90(ddd,4H)。MS(m/z)：483(MH +)。
Embodiment 10 1, the preparation of 2,3,4-tetrahydrochysene-2,4-dioxo-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide
In 100ml single port bottle, drop into uridylic-5-carboxylic acid (6g, 38mmol) and sulfur oxychloride (25ml) successively, be heated to 75 DEG C of reactions 2 hours.By concentrated for reaction solution dry, obtain yellow solid, solid sherwood oil is pulled an oar, and obtains 5.5g solid, i.e. uridylic-5-formyl chloride after filtering drying.
2-amino methylpyrimidine acetate (300mg is dropped in 25ml single port bottle, 1.8mmol), triethylamine (522mg, 5mmol) and N, N-dimethylformamide (5ml), stirring reaction is after 0.5 hour, add uridylic-5-formyl chloride (300mg, 1.7mmol).Be heated to 80 DEG C of reactions 1 hour, after reaction solution cooling, direct column chromatography, obtains target compound 320mg.
1HNMR(DMSO-d 6,400Hz):δ8.77(d,2H),8.17(s,1H),7.41(t,1H),4.57(d,2H)。
Embodiment 11 1, the preparation of 2,3,4-tetrahydrochysene-2,4-dioxo-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide
Uridylic-5-carboxylic acid, ethyl ester (3.0g, 16.29mmol), 2-amino methylpyrimidine (1.78g, 16.29mmol) are dissolved in methylene dichloride (50ml), stirred overnight at room temperature.Add methylene dichloride, water extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate to obtain crude product, obtain target compound 2.5g through purification by silica gel column chromatography, white solid, yield 62%.
1HNMR(DMSO-d 6，400Hz):δ8.77(d,2H),8.17(s,1H),7.41(t,1H),4.57(d,2H)。
The preparation of embodiment 12 avanaphil
1) preparation of 2,4-bis-chloro-N-(2-Pyrimidylmethyl)-5-pyrimidine carboxamide
Product (the 692mg of embodiment 10 is dropped in 25ml single port bottle, 2.8mmol), N, accelerine (292mg), phosphorus oxychloride (2.0mL) is added under ice bath cooling, be heated to 110 DEG C of reactions 3 hours, after question response liquid cooling but, be slowly poured into cancellation in frozen water.Aqueous phase dichloromethane extraction 2 times, merges organic phase, successively by water, saturated common salt washing organic phase, is concentrated into small volume, obtains reserve liquid after anhydrous sodium sulfate drying.
2) preparation of avanaphil
By chloro-for 3-4-methoxybenzylamine hydrochloride (0.59g, 2.8mmol) with triethylamine (0.29g, mixed solution 2.8mmol) is dropwise added drop-wise in above-mentioned reserve liquid, finish rear reaction 2 hours, L-Prolinol (0.43g is added again in reaction solution, 4.3mmol), room temperature reaction 4 hours.Reaction solution is poured into cancellation in frozen water, dichloromethane extraction 2 times, washes 2 times with water, anhydrous sodium sulfate drying after merging organic phase, the concentrated crude product column chromatography obtained obtains white solid 0.8g, i.e. avanaphil, yield 32%.
1HNMR(DMSO-d 6,400Hz):δ9.15(s,1H),8.75(d,2H),8.54(s,1H),7.32(m,1H),7.07(d,1H),4.57(s,2H),4.50(s,2H),4.11(s,1H),3.82(s,3H),3.51(m,5H),1.90(ddd,4H)。MS(m/z)：483(MH +)。
The preparation of the chloro-5-pyrimidine formyl chloride of embodiment 13 2,4-bis-
Add uridylic-5-carboxylic acid (1g, 6.4mmol), DMA (1.09g9.0mmol) successively to 25ml there-necked flask, under ice bath, dropwise add phosphorus oxychloride (9.83g, 64.1mmol).Drip the bath of recession deicing and be heated to 110 DEG C of reactions 4 hours, after question response liquid cooling but, slowly join cancellation in frozen water.Aqueous phase is extracted with ethyl acetate, and organic phases washed with water 2 times, washes 1 time with saturated common salt, anhydrous sodium sulfate drying, concentrated to obtain crude product 960mg, is oily matter, i.e. 2,4-bis-chloro-5 pyrimidinecarboxylic acids, is not purifiedly directly used in next step reaction.
1H NMR(CDCl 3,400MHz):δ9.18(s,1H),6.78(s,1H)。
In 50ml there-necked flask, add the crude product (0.6g, 3.1mmol) of upper step reaction successively, sulfur oxychloride (10ml), be heated to 80 DEG C of reactions 4 hours.Be evaporated to dry oily matter 0.6g, i.e. 2,4-bis-chloro-5-pyrimidine formyl chlorides, yield 90%.
1HNMR(CDCl 3,400MHz):δ9.24(s,1H)。
The preparation of embodiment 14 avanaphil
In 50ml there-necked flask, drop into 2,4-bis-chloro-5-pyrimidine formyl chloride (0.6g, 2.8mmol), methylene dichloride (8ml), ice bath is lowered the temperature.First 2-amino methylpyrimidine acetate (0.48g, 2.8mmol) and triethylamine (2.8mmol) are dissolved in methylene dichloride, are more dropwise added drop-wise in reaction solution.Finish, react 1 hour, by chloro-for 3-4-methoxybenzylamine hydrochloride (0.59g, 2.8mmol) with triethylamine (0.29g, mixed solution 2.8mmol) is dropwise added drop-wise in above-mentioned reaction solution, drips rear reaction 2 hours, then in reaction solution, add L-Prolinol (0.43g, 4.3mmol), room temperature reaction spends the night.Reaction solution is poured into cancellation in frozen water, dichloromethane extraction 2 times, washes 2 times with water, anhydrous sodium sulfate drying after merging organic phase, the crude product obtained after concentrated obtains white solid 0.9g through column chromatography, i.e. avanaphil, yield 64%.
1HNMR(DMSO-d 6,400Hz):δ9.15(s,1H),8.75(d,2H),8.54(s,1H),7.32(m,1H),7.07(d,1H),4.57(s,2H),4.50(s,2H),4.11(s,1H),3.82(s,3H),3.51(m,5H),1.90(ddd,4H)。MS(m/z)：483(MH +)。

Claims (9)

1. synthesize a method for avanaphil, described preparation method is one of following method:
Method one:
5-uridylic carboxylicesters (X) generates 2,4-dihalo-5-pyrimidine carboxylic ester (XI) through halogenating reaction;
Compounds X I and 3-chloro-4-methoxy benzylamine (II) or its salt generation substitution reaction, generate 2-halo-4-(3-chloro-4-methoxy benzamido group)-5-pyrimidine carboxylic ester (XII), it can carry out separation and purification, also can not be separated and be directly used in next step;
Compounds X II and L-dried meat ammonia alcohol (VI) carry out replacing further generating compound VI I,
Compound VI I and 2-pyrimidine ethamine (IX) or its salt generation ammonolysis reaction obtain avanaphil (I); Or,
Compound VI I is first hydrolyzed and obtains acid (VIII), then carries out amidate action with 2-pyrimidine ethamine (IX) or its salt and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 2:
reaction formula 2:
Wherein,
R is selected from the straight or branched alkyl of C1 ~ C6, the straight or branched alkyl of preferred C1 ~ C4, most preferable, ethyl or the tertiary butyl;
X is selected from halogen, is preferably chlorine or bromine;
Method two:
5-uridylic carboxylic acid (XIII) and 2-pyrimidine ethamine (IX) or its salt carry out amidate action or 5-uridylic carboxylicesters (X) and carry out ammonolysis reaction with 2-pyrimidine ethamine (IX) or its salt and obtain compounds X IV;
Compounds X IV obtains halides XV through halogenating reaction;
Halides XV and 3-chloro-4-methoxy benzylamine (II) or its salt generation substitution reaction generate compounds X VI;
Compounds X VI and L-dried meat ammonia alcohol (VI) carry out substitution reaction and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 3:
reaction formula 3:
Wherein,
R is selected from the straight or branched alkyl of C1 ~ C6, the straight or branched alkyl of preferred C1 ~ C4, most preferable, ethyl or the tertiary butyl;
X is selected from halogen, is preferably chlorine or bromine;
Method three:
5-uridylic carboxylic acid (XIII) is through halo and carboxylic acid activated reacting generating compound XVII;
Compounds X VII and 2-pyrimidine ethamine (IX) or its salt carry out ammonolysis reaction and generate compounds X V;
Compounds X V replaces further with 3-chloro-4-methoxy benzylamine (II) or its salt and generates compounds X VI;
Compounds X VI and L-dried meat ammonia alcohol (VI) carry out substitution reaction and obtain avanaphil (I),
Synthetic route is as shown in reaction formula 4:
reaction formula 4:
Wherein, X is selected from halogen, is preferably chlorine or bromine.
2. method according to claim 1, wherein, described substitution reaction is carried out in the presence of a base, and wherein, described alkali can be selected from mineral alkali, organic bases and its combination; Preferably, described mineral alkali is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrated barta, calcium hydroxide, cesium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, Strontium carbonate powder, cesium carbonate, sodium sulphite, sodium hydrogen and its combination; Described organic bases is selected from sodium alkoxide, potassium alcoholate, butyllithium, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, quinoline, DMAP, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine and its combination; More preferably, described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, potassium tert.-butoxide, pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine and its combination; The reaction solvent of described substitution reaction is selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent and other solvents; Preferably, described aromatic hydrocarbon solvent is selected from benzene,toluene,xylene, chlorobenzene, oil of mirbane and its combination; Described ether solvent is selected from tetrahydrofuran (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane and its combination; Described halogenated hydrocarbon solvent is selected from methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride and its combination; Other solvents described are selected from DMF, N,N-dimethylacetamide, methyl-sulphoxide, N-Methyl pyrrolidone, hexamethylphosphoramide, acetone, acetonitrile, ethyl acetate and its combination; Preferably, the temperature of reaction of described substitution reaction is-30 DEG C ~ 300 DEG C, more preferably-10 DEG C ~ 150 DEG C; Preferably, the reaction times of described substitution reaction is 1 ~ 12 hour.
3. method according to claim 1, wherein,
Described hydrolysis reaction carries out in presence of an acid; Preferably, described acid is selected from organic acid, mineral acid or its combination, is preferably selected from one or more in sulfuric acid, hydrochloric acid, hydrogen chloride gas, Hydrogen bromide, hydroiodic acid HI, phosphoric acid, nitric acid, formic acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid, perchloric acid; Or
Described hydrolysis reaction carries out in the presence of a base; Preferably, described alkali is selected from mineral alkali, organic bases and its combination; Preferably, described mineral alkali is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrated barta, calcium hydroxide, cesium hydroxide, sodium bicarbonate, saleratus, salt of wormwood, sodium carbonate, Strontium carbonate powder, cesium carbonate and its combination; Described organic bases is selected from Potassium ethanoate, sodium-acetate, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, quinoline, DMAP, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine and its combination; Preferably, described alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, salt of wormwood, sodium carbonate and its combination; Preferably, the solvent of described hydrolysis reaction is for being selected from water, C 1~ C 5alcohol, N, dinethylformamide, N, one or more in N-N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, tetrahydrofuran (THF), acetonitrile, dioxane, morpholine, N-Methyl pyrrolidone, methylene dichloride, chloroform, glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, are preferably selected from one or more in water, methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane; The temperature of reaction of described hydrolysis reaction preferably at-10 DEG C ~ 300 DEG C, between more preferably 0 DEG C ~ 100 DEG C; The reaction times of described hydrolysis reaction preferably at 10 minutes ~ 24 hours, more preferably between 0.5 ~ 10 hour.
4. method according to claim 1, wherein, described halogenating reaction carries out under halogenating agent exists; Preferably, described halogenating agent is be selected from one or more in phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, chlorine, bromine, iodine and tribromo oxygen phosphorus; Described halogenating reaction is having or is carrying out under the existence of reactionless solvent, described reaction solvent is preferably selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide; The temperature of reaction of described halogenating reaction preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 150 DEG C.
5. method according to claim 1, wherein, described halo and carboxylic acid activated reaction are carried out under halogenating agent exists; Preferably, described halogenating agent is be selected from one or more in sulfur oxychloride, thionyl bromide, pivaloyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride and tribromo oxygen phosphorus; Described halo and carboxylic acid activated reaction are having or are carrying out under the existence of reactionless solvent, described reaction solvent is preferably selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide; The temperature of reaction of described halo and carboxylic acid activated reaction preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 150 DEG C.
6. method according to claim 1, wherein, described ammonolysis reaction is having or under alkali-free existence, is carrying out in a solvent; Preferably, described alkali is for being selected from pyridine, piperidines, tetramethyleneimine, morpholine, N-methylmorpholine, quinoline, DMAP, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, sodium methylate, sodium ethylate, potassium tert.-butoxide, butyllithium, 1,8-diazacyclo [5,4,0] one or more in hendecene-7, N-methylmorpholine, quinoline, DMAP, sodium hydrogen, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, saleratus, sodium carbonate and salt of wormwood; Preferably, the reaction solvent of described ammonolysis reaction is selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, other solvents and its combination; Preferably, described aromatic hydrocarbon solvent is be selected from one or more in benzene,toluene,xylene etc.; Described ether solvent is be selected from one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane; Described halogenated hydrocarbon solvent is be selected from one or more in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride; Other solvents described are be selected from one or more in methyl alcohol, ethanol, ethylene glycol, normal hexane, hexanaphthene, DMF, N,N-dimethylacetamide, methyl-sulphoxide, N-Methyl pyrrolidone, acetone, acetonitrile, ethyl acetate; The temperature of reaction of described ammonolysis reaction preferably at-30 DEG C ~ 150 DEG C, between more preferably-10 DEG C ~ 120 DEG C; The reaction times of described ammonolysis reaction is preferably between 10 minutes ~ 24 hours.
7. method according to claim 1, wherein, described amidate action carries out as follows: having or under catalyst-free existence, reacting and generate carboxylic acid halides, then carry out ammonolysis reaction with amine with halogenating agent; Preferably, described halogenating agent is be selected from one or more in sulfur oxychloride, oxalyl chloride, thionyl bromide, phosphorus oxychloride, tribromo oxygen phosphorus, phosphorus trichloride, phosphorus pentachloride, pivaloyl chloride; Described catalyzer is be selected from one or more in DMF, Diethyl Aniline, xylidine; The reaction of described generation carboxylic acid halides is having or is carrying out under the existence of reactionless solvent, described reaction solvent is preferably selected from methylene dichloride, methyl-sulphoxide, tetrahydrofuran (THF), benzene, toluene, chloroform, dimethylbenzene, N, one or more in dinethylformamide, N,N-dimethylacetamide; The temperature of reaction of the reaction of described generation carboxylic acid halides preferably at-30 DEG C ~ 300 DEG C, between more preferably-5 DEG C ~ 100 DEG C.
8. method according to claim 1, wherein, described amidate action carries out as follows: use condensing agent, is having or under catalyst-free condition, is having or carry out under alkali-free existence; Described condensing agent is preferably selected from N, N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide, phosphinylidyne diimidazole, N, N'-DIC, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, one or more in N', N'-tetramethyl-urea phosphofluoric acid ester, benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate; Described catalyzer is preferably selected from one or more in 1-hydroxyl-benzotriazole, 4-dimethylamino pyridine; Described alkali is preferably selected from triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, Trimethylamine 99, pyridine, 2,6-lutidine, DMAP, piperidines, tetramethyleneimine, quinoline, morpholine, N-methylmorpholine, N-ethylmorpholine, diisopropylamine, diisopropylethylamine, 1,8-diazacyclo [5,4,0] one or more in hendecene-7 and 1,5-diazabicylo [the 4.3.0]-ninth of the ten Heavenly Stems-5-alkene; Reaction solvent is preferably selected from benzene, dimethylbenzene, toluene, methylene dichloride, chloroform, tetrahydrofuran (THF), ether, propyl ether, 1,4-dioxane, N, dinethylformamide, N, N-diethylformamide, N, the mixture of N-N,N-DIMETHYLACETAMIDE, acetonitrile, methyl-sulphoxide and above-mentioned solvent, be more preferably tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, N,N-dimethylacetamide or methyl-sulphoxide; Temperature of reaction preferably at-20 DEG C ~ 200 DEG C, between more preferably-10 DEG C ~ 100 DEG C.
9. a midbody compound, it is one of following compounds:
Wherein, X is selected from halogen independently of one another, is preferably chlorine or bromine independently of one another.
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