CN104650045B - Preparation method of avanafil - Google Patents

Preparation method of avanafil Download PDF

Info

Publication number
CN104650045B
CN104650045B CN201410653978.8A CN201410653978A CN104650045B CN 104650045 B CN104650045 B CN 104650045B CN 201410653978 A CN201410653978 A CN 201410653978A CN 104650045 B CN104650045 B CN 104650045B
Authority
CN
China
Prior art keywords
reaction
acid
sodium
potassium
ether
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201410653978.8A
Other languages
Chinese (zh)
Other versions
CN104650045A (en
Inventor
田广辉
李军奇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suzhou Wangshan Wangshui Biopharmaceutical Co ltd
Original Assignee
Suzhou Vigonvita Life Sciences Co ltd
Topharman Shanghai Co Ltd
Topharman Shandong Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suzhou Vigonvita Life Sciences Co ltd, Topharman Shanghai Co Ltd, Topharman Shandong Co Ltd filed Critical Suzhou Vigonvita Life Sciences Co ltd
Priority to CN201410653978.8A priority Critical patent/CN104650045B/en
Publication of CN104650045A publication Critical patent/CN104650045A/en
Application granted granted Critical
Publication of CN104650045B publication Critical patent/CN104650045B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 avanaphil (avanafil), (which is a kind of PDE5 suppressions Preparation, i.e. 5 type phosphodiesterase inhibitors) preparation method, the noval chemical compound provided in further relating to preparation process.
Background technology
Avanaphil (avanafil) is to authorize the exploitation of Vivus companies of the U.S. by Japanese Tanabe Mitsubishi Pharmaceutical Co For treating high selectivity phosphodiesterase -5 (PDE-5) inhibitor of male erectile dysfunction (ED), in April 27 in 2012 The approval of Nikkei U.S. FDA is listed in the U.S., trade name Stendra.The medical instrument has and other PDE-5 inhibitor identical effects Mechanism, but with unique pharmacokineticss and pharmacodynamic profiles, it is advantageous that oral absorption faster, many ED patients are using this Can successfully carry out sexual life after product in 0.5 hour, it is equivalent or better than other PDE-5 inhibitor in the market, such as west That non-(trade name:Viagra), Vardenafil (trade name:Levitra), tadanafil (trade name:Tadalafil) etc., viagra and Chinese mugwort About 30 minutes onset time of the power up to after taking, Tadalafil are 2 hours, therefore, the quick-acting advantages of avanaphil can make it more Favored by ED patient.And the high selectivity of avanaphil then causes its side effect less compared with other like products, its backache and The incidence rates such as audiovisual obstacle are relatively low.
Avanaphil synthetic route disclosed in international patent application WO2001019802A1 is 3- chloro-4-methoxy benzylamines (II) there is nucleophilic substitution with the chloro- 2- methylthiopyrimidines -5- carboxylic acid, ethyl esters (III) of 4- and obtain 4- (3- chloro-4-methoxy benzyls Amido) -2- methylthiopyrimidines -5- carboxylic acid, ethyl esters (IV), then compound IV metachloroperbenzoic acids (mCPBA) is aoxidized To 4- (3- chloro-4-methoxy benzamido groups) -2- methanesulfonyl pyrimidines -5- carboxylic acid, ethyl esters (V), by compound V and L- dried meat ammonia alcohol it is (S) -2- hydroxymethyl pyrrolidines (VI) generation substitution reaction obtains compound VII, with 2- pyrimidine ethamine after compound VII hydrolysis (IX) carry out amidation process and obtain avanaphil, synthetic route is as shown in reaction equation 1：
Reaction equation 1：
In the route, the price of the chloro- 2- methylthiopyrimidines -5- carboxylic acid, ethyl esters (III) of raw material 4- costly uses m-chloro mistake Easily produce during oxybenzoic acid (mCPBA) oxidation 4- (3- chloro-4-methoxy benzamido groups) -2- methylthiopyrimidine -5- carboxylic acid, ethyl esters (IV) The impurity that raw difficulty is removed, and 4- (3- chloro-4-methoxy benzamido groups) -2- methanesulfonyl pyrimidines -5- carboxylic acid, ethyl esters (V) and L- dried meat ammonia alcohol (VI) reaction yield is too low.
As above-mentioned preparation method has high cost, yield is low, more than impurity and the shortcomings of being not readily separated, it is therefore necessary to seek Economic, practical, environmentally friendly, stable, reasonable a variation route is looked for, to improve technology stability, reduces cost, raising product Quality.
The content of the invention
For above-mentioned weak point, it is an object of the present invention to provide a kind of new method for preparing avanaphil, is somebody's turn to do Method utilizes raw material cheap and easy to get and reagent, can synthesize the avanaphil for meeting clinical demand at lower cost, and Easy to operate, reaction condition is gentle, high income, low cost, it is environmentally friendly, be adapted to industrialization large-scale production avanaphil.
It is a further object of the present invention to provide the new compound being related in above-mentioned preparation method.
To achieve these goals, the invention provides with 5- uracil carboxylic acid or its ester as Material synthesis avanaphil Method, the preparation method are one of following method：
Method one：
5- uracil carboxylate (X) Jing halogenating reactions generate 2,4- dihalos -5- pyrimidine carboxylic esters (XI)；
There is substitution reaction in compounds X I and 3- chloro-4-methoxy benzylamines (II) or its salt, (3- is chloro- to generate 2- halos -4- 4- methoxybenzyl amidos) -5- pyrimidine carboxylic esters (XII), which can be isolated and purified, can not also separate be directly used in it is next Step；
Compounds X II and L- dried meat ammonia alcohol (VI) is further substituted with generating compound VII,
Avanaphil (I) obtained and ammonolysis reaction in compound VII and 2- pyrimidine ethamine (IX) or its salt there is；Or,
Compound VII is first hydrolyzed and is obtained sour (VIII), then is carried out amidation process with 2- pyrimidine ethamine (IX) or its salt and obtained To avanaphil (I),
Synthetic route is as shown in reaction equation 2：
Reaction equation 2：
Wherein,
Straight or branched alkyls of the R selected from C1～C6, the straight or branched alkyl of preferred C1～C4, most preferable, second Base or the tert-butyl group；
X is selected from halogen, preferably chlorine or bromine；
Method two
5- uracil carboxylic acids (XIII) and 2- pyrimidine ethamine (IX) or its salt carry out amidation process or 5- uracil carboxylics Acid esters (X) carries out ammonolysis reaction and obtains compounds X IV with 2- pyrimidine ethamine (IX) or its salt；
Compounds X IV Jing halogenating reactions obtain halides XV；
Compounds X VI generated and substitution reaction with 3- chloro-4-methoxy benzylamines (II) or its salt in halides XV there is；
Compounds X VI and L- dried meat ammonia alcohol (VI) carries out substitution reaction and obtains avanaphil (I),
Synthetic route is as shown in reaction equation 3：
Reaction equation 3：
Wherein,
Straight or branched alkyls of the R selected from C1～C6, the straight or branched alkyl of preferred C1～C4, most preferable, second Base or the tert-butyl group；
X is selected from halogen, preferably chlorine or bromine；
Method three：
5- uracil carboxylic acids (XIII) Jing halos 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 and 3- chloro-4-methoxy benzylamines (II) or its salt are further substituted with generating compounds X VI；
Compounds X VI and L- dried meat ammonia alcohol (VI) carries out substitution reaction and obtains avanaphil (I),
Synthetic route is as shown in reaction equation 4：
Reaction equation 4：
Wherein, X is selected from halogen, preferably chlorine or bromine.
In the above-mentioned methods, described substitution reaction can be carried out in the presence of a base, wherein, the alkali can be selected from inorganic Alkali, organic base and its combination.For example, inorganic basis such as can selected from sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, Barium hydroxide, calcium hydroxide, Cesium hydrate., sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sulfuration Sodium, sodium hydrogen etc. and its combination；Organic bases such as can be selected from sodium alkoxide, potassium alcoholate, butyl lithium, 1,8- diazacyclos [5,4,0] 11 Alkene -7 (DBU), pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, quinoline, DMAP (DMAP), triethylamine, Diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine etc. and its combination.Wherein, sodium alkoxide for example can be with Selected from Feldalat NM, Sodium ethylate, sodium propoxide, sodium isopropylate, n-butyl alcohol sodium, sodium tert-butoxide etc. and its combination；Potassium alcoholate can for example be selected From Feldalat KM, potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butyl alcohol potassium, potassium tert-butoxide etc. and its combination.The alkali is preferably selected from hydrogen Sodium oxide, potassium hydroxide, Lithium hydrate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, Feldalat NM, Sodium ethylate, the tert-butyl alcohol Potassium, pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine and its Combination.The reaction dissolvent of the substitution reaction may be selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent and other solvents. Wherein, the aromatic hydrocarbon solvent for example can be selected from benzene,toluene,xylene, chlorobenzene, Nitrobenzol etc. and its combination；The ethers Solvent for example can selected from tetrahydrofuran (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether, Dioxane etc. and its combination；The halogenated hydrocarbon solvent can for example be selected from dichloromethane, chloroform, carbon tetrachloride, two chloroethenes Alkane etc. and its combination；Described other solvents for example can selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide, Dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, hexamethyl phosphoramide, acetone, acetonitrile, ethyl acetate etc. and its combination.But this Invention is not limited to above-mentioned solvent.The reaction temperature of the substitution reaction is not particularly limited, preferably -30 DEG C～300 DEG C of temperature Degree scope, more preferably -10 DEG C～150 DEG C.The response time of the substitution reaction is not particularly limited, preferably 1～12 hour.
In the above-mentioned methods, described hydrolysis can be carried out in presence of an acid.The acid can be selected from organic acid, inorganic Acid or its combination, for example, selected from sulphuric acid, hydrochloric acid, hydrogen chloride gas, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid, acetic acid, One or more in trichloroacetic acid, trifluoroacetic acid, perchloric acid etc., but it is not limited to above-mentioned acid.The hydrolysis also can be Carry out in the presence of alkali.The alkali can be selected from inorganic base, organic base and its combination.The inorganic basis can such as be selected from hydroxide Sodium, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, calcium hydroxide, Cesium hydrate., sodium bicarbonate, potassium bicarbonate, carbon Sour potassium, sodium carbonate, strontium carbonate, cesium carbonate and its combination.The organic bases can such as be selected from potassium acetate, sodium acetate, 1,8- bis- Azacyclo- [5,4,0] hendecene -7 (DBU), pyridine, quinoline, DMAP (DMAP), triethylamine, diethylamine, three just Butylamine, tripropylamine, diisopropylamine or diisopropylethylamine etc. and its combination.It is preferred that the alkali is selected from sodium hydroxide, hydrogen-oxygen Change potassium, Lithium hydrate, potassium carbonate, sodium carbonate and its combination.The hydrolysis can be carried out in appropriate solvent.The solvent Can be selected from water, C1～C5Alcohol (for example methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, Isoamyl alcohol, ethylene glycol, Propylene Glycol, glycerol etc. or its combination), N,N-dimethylformamide (DMF), N, N- dimethylacetamides Amine, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, morpholine, N-Methyl pyrrolidone, dichloromethane, chlorine One or more in imitative, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether etc., preferred water, methanol, ethanol, One or more in tetrahydrofuran (THF), dioxane.The reaction temperature of the hydrolysis is not particularly limited, but It is preferred that at -10 DEG C～300 DEG C, between more preferably 0 DEG C～100 DEG C.The response time of the hydrolysis is not particularly limited, but It is preferably at 10 minutes～24 hours, more preferably between 0.5～10 hour.
In the above-mentioned methods, described halogenating reaction is carried out in the presence of halogenating agent.The halogenating agent can be choosing One or more from phosphorus oxychloride, phosphorus pentachloride, Phosphorous chloride., chlorine, bromine, iodine and tribromo oxygen phosphorus.The halo is anti- Should carry out in the presence of with or without reaction dissolvent, the reaction dissolvent is not particularly limited, if its not disturbing reaction be Can, can for example be selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N, N- dimethyl methyls One or more in amide, DMAC N,N' dimethyl acetamide etc..The reaction temperature of the halogenating reaction is not particularly limited, but It is preferred that at -30 DEG C～300 DEG C, between more preferably -5 DEG C～150 DEG C.
In the above-mentioned methods, the halo and carboxylic acid activated reaction is carried out in the presence of halogenating agent.The halogenating agent Can be selected from thionyl chloride, thionyl bromide, pivaloyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, Phosphorous chloride. or tribromo One or more in oxygen phosphorus.The halo and carboxylic acid activated reaction can be carried out in the presence of with or without reaction dissolvent, described Reaction dissolvent be not particularly limited, as long as its not disturbing reaction, can for example be selected from dichloromethane, dimethyl sulfoxide, One kind or many in tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide etc. Kind.The reaction temperature of described halo and carboxylic acid activated reaction is not particularly limited, it is preferred that at -30 DEG C～300 DEG C, it is more excellent Between -5 DEG C～150 DEG C of choosing.
In the above-mentioned methods, described ammonolysis reaction in the presence of a base, is carried out in appropriate solvent.Described alkali can be with It is selected from pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, quinoline, DMAP (DMAP), triethylamine, diethyl Amine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, Feldalat NM, Sodium ethylate, potassium tert-butoxide, butyl lithium, 1, 8- diazacyclos [5,4,0] hendecene -7 (DBU), N-methylmorpholine, quinoline, DMAP (DMAP), sodium hydrogen, hydrogen-oxygen Change one or more in sodium, potassium hydroxide, Lithium hydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.The ammonia The reaction dissolvent of solution reaction may be selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, other solvents and its combination.Wherein, The aromatic hydrocarbon solvent can for example be one or more in benzene,toluene,xylene etc.；The ether solvent for example may be used Think selected from tetrahydrofuran (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether, dioxane One or more in；The halogenated hydrocarbon solvent can for example be selected from dichloromethane, chloroform, carbon tetrachloride, two chloroethenes One or more in alkane etc.；Described other solvents can for example be selected from methanol, ethanol, ethylene glycol, normal hexane, hexamethylene, N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone, acetone, second One or more in nitrile, ethyl acetate etc., but the present invention is not limited to above-mentioned solvent.The reaction temperature of the ammonolysis reaction does not have There is particular restriction, it is preferred that at -30 DEG C～150 DEG C, between more preferably -10 DEG C～120 DEG C.During the reaction of the ammonolysis reaction Between be not particularly limited, it is preferred that between 10 minutes～24 hours.
In the above-mentioned methods, described amidation process can be carried out using two methods.The first amidation method be In the presence of with or without catalyst, carboxylic acid halides is generated with halogenating agent reaction, then carry out ammonolysis reaction with amine.Described halogenating agent can Think selected from thionyl chloride, oxalyl chloride, thionyl bromide, phosphorus oxychloride, tribromo oxygen phosphorus, Phosphorous chloride., phosphorus pentachloride, pivaloyl chloride One or more in.Described catalyst can be selected from N,N-dimethylformamide (DMF), diethylaniline, diformazan One or more in base aniline etc..The reaction for generating carboxylic acid halides can be carried out in the presence of with or without reaction dissolvent, described Reaction dissolvent be not particularly limited, as long as its not disturbing reaction, can for example be selected from dichloromethane, dimethyl sulfoxide, One kind or several in tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide etc. Kind.The reaction temperature of the reaction for generating carboxylic acid halides is not particularly limited, it is preferred that at -30 DEG C～300 DEG C, more preferably -5 DEG C Between～100 DEG C.The condition of the ammonolysis reaction is as described above.
Second amidation method is to use condensing agent, under with or without catalysts conditions, is carried out in the presence of a base.It is described Condensing agent can be that, selected from N, N'- dicyclohexylcarbodiimides (DCC), 1- ethyl -3- (3- dimethylamino-propyls) carbon two are sub- Amine (EDCl), phosphinylidyne diimidazole (CDI), N, N'- DIC (DIC), O- BTA-N, N, N', N'- tetra- TBTU (TBTU), O- (7- azo BTAs)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), BTA -1- bases epoxide three (two Methylamino) one or more in phosphorus hexafluorophosphate (BOP).Described catalyst can be selected from 1- hydroxyls-benzo One or more in triazole (HOBt), 4- dimethylamino pyridines (DMAP) etc..The alkali can be selected from triethylamine, diethyl Amine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, trimethylamine, pyridine, 2,6- lutidines, 4- bis- Methylamino pyridine, piperidines, pyrrolidine, quinoline, morpholine, N-methylmorpholine, N-ethylmorpholine, diisopropylamine, diisopropyl second In amine, 1,8- diazacyclos [5,4,0] hendecene -7 (DBU) or 1,5- diazabicylos [4.3.0]-nonyl- 5- alkene (DBN) etc. One or more.The reaction dissolvent of second amidation method can be selected from：Hydro carbons, such as benzene, dimethylbenzene, toluene, two Chloromethanes or chloroform；Ethers, such as tetrahydrofuran, ether, propyl ether or Isosorbide-5-Nitrae-dioxane；Amide-type, such as N, N- dimethyl formyls Amine, N, N- diethylformamide or DMAC N,N' dimethyl acetamide；Nitrile, such as acetonitrile；Other, such as dimethyl sulfoxide etc.；And it is above-mentioned The mixture of solvent, wherein, preferred reaction dissolvent be tetrahydrofuran, acetonitrile, dichloromethane, DMF, N, N- dimethyl acetylamide or dimethyl sulfoxide.The reaction temperature of second amidation method is not particularly limited, as long as not shadow Ringing reaction is carried out, it is preferred that 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 each independently selected from halogen, is preferably each independently chlorine or bromine.
Three routes of the present invention have passed through 2 step substitution reactions, make use of on pyrimidine ring 4 halogens than 2 halogens Vivaciously, so reaction sequence is all 4 elder generations of double halides and the chloro- 4- emilium tosylates of 3- or its reactant salt, then it is 2 of pyrimidine React with L- dried meat ammonia alcohol.
It is an advantage of the current invention that using raw material cheap and easy to get and reagent, easy operation, gentle reaction bar Part produces high-quality avanaphil, and the process route can be used for the big production of scale.
Specific embodiment
The present invention is illustrated below with reference to embodiment this is more easily understood in order to those skilled in the art It is bright, but the present invention is not limited to the following example.
Embodiment
The preparation of 1 2,4- of embodiment, bis- chloro- 5- pyrimidinecarboxylicacidethylesters
To in 100ml there-necked flasks, uracil -5- carboxylic acid, ethyl esters (2.2g, 11.95mmol), N, N- dimethyl benzene are added Amine (2g, 16.50mmol).Phosphorus oxychloride (9.2g, 60mmol) is gradually added under ice bath, and is stirred continuously.Stir after completion of dropping 10min is mixed, is gradually heated up 110 DEG C, and be incubated 3h reactions.Reactant liquor is poured slowly in mixture of ice and water (100ml) and is quenched, And be stirred continuously, maintain the temperature at less than 5 DEG C.It is extracted twice with ethyl acetate (200ml).Organic faciess merge, and use saturated brine Washing, drying are concentrated to give crude product.Crude product Jing column chromatographies obtain solid 1.8g, yield 68%.
1H NMR(DMSO-d6,400MHz):δ9.13(s,1H),4.37(q,2H),1.32(t,3H)。
The preparation of 2 2,4- of embodiment, the bis- chloro- 5- pyrimidine carboxylics tert-butyl esters
To in 100ml there-necked flasks, uracil -5- carboxylic acid tert-butyl esters (2.5g, 11.95mmol), N, N- dimethyl are added Aniline (2g, 16.50mmol).Phosphorus oxychloride (9.2g, 60mmol) is gradually added under ice bath, and is stirred continuously.After completion of dropping Stirring 10min, gradually heats up 110 DEG C, and is incubated 3h reactions.It is concentrated to dryness, adds saturated sodium bicarbonate solution (100ml), protects Temperature is held below 5 DEG C.It is extracted twice with ethyl acetate (200ml).Organic faciess merge, and are washed with saturated brine, are dried concentration Obtain crude product.Crude product Jing column chromatographies obtain solid 1.9g, yield 65%.
1H NMR(DMSO-d6,400MHz):δ9.13(s,1H),1.43(s,9H).MS(m/z)：250(MH+)。
3 4- of embodiment (3- chloro-4-methoxy benzamido groups) -2- [(S) -2- hydroxymethylpyrrols alkyl -1-] -5- pyrimidine carboxylics The preparation of acetoacetic ester
To in 25ml there-necked flasks, 2,4-, bis- chloro- 5- pyrimidinecarboxylicacidethylesters (150mg, 0.679mmol) are sequentially added, three Ethamine (270mg, 2.668mmol), dichloromethane (2ml) are gradually stirred to dissolving, and ice bath is cooled to less than 0 DEG C, to reactant liquor In the chloro- 4- methoxybenzylamine hydrochlorides (145mg, 0.697mmol) of 3- that are dividedly in some parts, charging finishes rear thermal reacting for two hours. L- dried meat ammonia alcohol (105mg, 1.038mmol) is added dropwise in reactant liquor again, is finished, continue stirring reaction 2 hours.By reactant liquor Water (30ml) is added to, is extracted with dichloromethane.Merge organic faciess, twice, anhydrous sodium sulfate drying filters desiccant for washing, Concentration organic faciess obtain crude product.Crude product Jing silica gel column chromatography (petroleum ether：Ethyl acetate=6:1) product 200mg, yield 70% are obtained.1H NMR(DMSO-d6,400Hz):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+)。
4 4- of embodiment (3- chloro-4-methoxy benzamido groups) -2- [(S) -2- hydroxymethylpyrrols alkyl -1-] -5- pyrimidine carboxylics The preparation of tert-butyl acrylate
To in 25ml there-necked flasks, 2,4-, the bis- chloro- 5- pyrimidine carboxylics tert-butyl esters (169mg, 0.679mmol) are sequentially added, Triethylamine (270mg, 2.668mmol), dichloromethane (2ml) are gradually stirred to dissolving, and ice bath is cooled to less than 0 DEG C, to reaction The chloro- 4- methoxybenzylamine hydrochlorides (145mg, 0.697mmol) of 3- being dividedly in some parts in liquid, it is little that charging finishes rear insulation reaction two When.L- dried meat ammonia alcohol (105mg, 1.038mmol) is added dropwise in reactant liquor again, is finished, continue stirring reaction 2 hours.Will be anti- Answer liquid to be added to water (30ml), extracted with dichloromethane.Merge organic faciess, twice, anhydrous sodium sulfate drying filters drying for washing Agent, concentration organic faciess obtain crude product.Crude product Jing silica gel column chromatographies obtain product 228mg, yield 75%.
1HNMR(DMSO-d6,400Hz):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+)。
5 4- of embodiment (3- chloro-4-methoxy benzamido groups) -2- [(S) -2- hydroxymethylpyrrols alkyl -1-] -5- pyrimidine carboxylics The preparation of acid
To in 250ml there-necked flasks, the product (3.4g, 8.095mmol) of embodiment 3, dimethyl sulfoxide are sequentially added (34ml), the lower stirring of ice bath cooling is extremely dissolved, then gradually Deca 10%NaOH aqueous solution (23ml) in reactant liquor.Drip Afterwards, it is warmed to room temperature, is stirred overnight.To 10% acetic acid solution of Deca in reactant liquor under ice bath, pH to 6～7 or so is adjusted, stir 0.5h Separate out white solid.Filter, tetrahydrofuran beating, sucking filtration obtain white solid, dry to obtain object 2.23g, yield 70%.
1HNMR(DMSO-d6,400Hz):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+)。
6 4- of embodiment (3- chloro-4-methoxy benzamido groups) -2- [(S) -2- hydroxymethylpyrrols alkyl -1-] -5- pyrimidine carboxylics The preparation of acid
The product (5.0g, 11.14mmol) of embodiment 4, dichloromethane/trifluoroacetic acid are added in 100mL eggplant-shape bottles (30ml, V/V=1:1), it is stirred overnight at room temperature.Concentration of reaction solution, is slowly added dropwise saturated sodium bicarbonate aqueous solution and adjusts pH to 6～7 Left and right, stirring 0.5h separate out white solid.Filter, tetrahydrofuran beating, sucking filtration obtains white solid, dry object (3.8g, 87%).
1HNMR(DMSO-d6,400Hz):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 7 avanaphil of embodiment
To in 50ml there-necked flasks put into 2- amino methylpyrimidine acetate (0.65g, 3.846mmol), triethylamine (0.36g, 3.558mmol) with DMF (10ml), 0.5h is stirred.Sequentially add the product of embodiment 5 again in reactant liquor (1.00g, 2.550mmol), EDCI (0.54g, 2.817mmol) and I-hydroxybenzotriazole (0.38g, 2.812mmol), room temperature Stirring reaction 8 hours.Reactant liquor is poured in sodium bicarbonate solution, and is extracted with ethyl acetate.Merge organic faciess, saturation food Salt is washed, anhydrous sodium sulfate drying, filters desiccant, and concentration organic faciess obtain crude product.Crude product recrystallization obtains avanaphil 0.74g, Yield 60%.
1HNMR(DMSO-d6,400Hz):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 8 avanaphil of embodiment
Under room temperature condition, the product (1.2g, 3.1mmol) of embodiment 5, protochloride are sequentially added in 50ml there-necked flasks Sulfone (10ml), is heated to 80 DEG C and reacts 4 hours.It is evaporated to dry 4- (3- chloro-4-methoxy benzamido groups) -2- [(S) -2- Hydroxymethylpyrrol alkyl -1-] -5- pyrimidine formyl chlorides, solid 1.2g, yield 95%.
In 50ml there-necked flasks, addition 2- amino methylpyrimidines (318mg, 2.92mmol), triethylamine (1.2ml, 8.43mmol), dichloromethane (8ml), is slowly added dropwise the two of step reaction gained crude product (1.2g, 2.92mmol) under condition of ice bath Chloromethanes (5ml) solution, adds and is stirred overnight at room temperature.Add dichloromethane, water to extract 2 times, after merging organic faciess, wash 2 with water Secondary, anhydrous sodium sulfate drying is concentrated to give crude product.Crude product Jing column chromatographies obtain white solid 0.9g, i.e. avanaphil, yield 64%.
1HNMR(DMSO-d6,400Hz):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 9 avanaphil of embodiment
By the product (2.0g, 4.75mmol) of embodiment 3,2- amino methylpyrimidines (537mg, 4.75mmol), two are dissolved in Chloromethanes (20ml), are stirred overnight at room temperature.Dichloromethane, water extraction are added, merge organic faciess, anhydrous sodium sulfate drying is filtered, Crude product is concentrated to give, Jing silica gel column chromatography purification obtains white solid 1.0g, i.e. avanaphil, yield 44%.
1HNMR(DMSO-d6,400Hz):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 10 1,2,3,4- tetrahydrochysene -2,4- dioxo-N- (2- Pyrimidylmethyls) -5- pyrimidine carboxamides of embodiment
Put into uracil -5- carboxylic acids (6g, 38mmol) and thionyl chloride (25ml) in 100ml single port bottles successively, heat React 2 hours to 75 DEG C.Will be reactant liquor concentration dry, yellow solid is obtained, solid is beaten with petroleum ether, and 5.5g is obtained after filtering drying Solid, i.e. uracil -5- formyl chlorides.
In 25ml single port bottles put into 2- amino methylpyrimidine acetate (300mg, 1.8mmol), triethylamine (522mg, 5mmol) and DMF (5ml), stirring reaction is after 0.5 hour, add uracil -5- formyl chlorides (300mg, 1.7mmol).It is heated to 80 DEG C to react 1 hour, after reactant liquor cooling, direct column chromatography, obtains object 320mg.
1HNMR(DMSO-d6,400Hz):δ8.77(d,2H),8.17(s,1H),7.41(t,1H),4.57(d,2H)。
The preparation of 11 1,2,3,4- tetrahydrochysene -2,4- dioxo-N- (2- Pyrimidylmethyls) -5- pyrimidine carboxamides of embodiment
By uracil -5- carboxylic acid, ethyl esters (3.0g, 16.29mmol), 2- amino methylpyrimidines (1.78g, 16.29mmol) are molten In dichloromethane (50ml), it is stirred overnight at room temperature.Dichloromethane, water is added to extract, merging organic faciess, anhydrous sodium sulfate drying, Filter, be concentrated to give crude product, Jing silica gel column chromatography purification obtains target compound 2.5g, white solid, yield 62%.
1HNMR(DMSO-d6, 400Hz):δ8.77(d,2H),8.17(s,1H),7.41(t,1H),4.57(d,2H).
The preparation of 12 avanaphil of embodiment
1) preparation of bis- chloro- N- of 2,4- (2- Pyrimidylmethyls) -5- pyrimidine carboxamides
Product (692mg, 2.8mmol), the N of embodiment 10, accelerine are put in 25ml single port bottles (292mg), ice bath cooling is lower adds phosphorus oxychloride (2.0mL), is heated to 110 DEG C and reacts 3 hours, after the cooling of question response liquid slowly It is quenched in being poured into frozen water.Water is extracted 2 times with dichloromethane, merges organic faciess, organic with water, saturated common salt washing successively Phase, is concentrated into small size, obtains reserve liquid after anhydrous sodium sulfate drying.
2) preparation of avanaphil
By 3- chloro- 4- methoxybenzylamine hydrochlorides (0.59g, 2.8mmol) and the mixed liquor of triethylamine (0.29g, 2.8mmol) Dropwise be added drop-wise in above-mentioned reserve liquid, after finishing react 2 hours, then in reactant liquor add L- Prolinols (0.43g, 4.3mmol), room temperature reaction 4 hours.Reactant liquor is poured in frozen water and is quenched, dichloromethane is extracted 2 times, after merging organic faciess Wash with water 2 times, anhydrous sodium sulfate drying, the crude product column chromatography being concentrated to give obtains white solid 0.8g, i.e. avanaphil, yield 32%.
1HNMR(DMSO-d6,400Hz):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 13 2,4- of embodiment, bis- chloro- 5- pyrimidines formyl chlorides
Uracil -5- carboxylic acids (1g, 6.4mmol), N, accelerine are sequentially added to 25ml there-necked flasks (1.09g9.0mmol) phosphorus oxychloride (9.83g, 64.1mmol) is added dropwise under ice bath,.Dripping recession goes ice bath to heat React 4 hours to 110 DEG C, be quenched in frozen water being slowly added into after the cooling of question response liquid.Water is mutually extracted with ethyl acetate, organic faciess Wash with water 2 times, washed 1 time with saturated common salt, anhydrous sodium sulfate drying is concentrated to give crude product 960mg, is grease, i.e. 2,4- bis- Chloro- 5 pyrimidinecarboxylic acid, it is not purified to be directly used in next step reaction.
1H NMR(CDCl3,400MHz):δ9.18(s,1H),6.78(s,1H)。
Sequentially add the crude product (0.6g, 3.1mmol) of upper step reaction in 50ml there-necked flasks, thionyl chloride (10ml), It is heated to 80 DEG C to react 4 hours.It is evaporated to dry grease 0.6g, i.e. 2,4-, bis- chloro- 5- pyrimidines formyl chlorides, yield 90%.
1HNMR(CDCl3,400MHz):δ9.24(s,1H)。
The preparation of 14 avanaphil of embodiment
Put into 2,4-, bis- chloro- 5- pyrimidines formyl chlorides (0.6g, 2.8mmol) in 50ml there-necked flasks, dichloromethane (8ml), Ice bath is lowered the temperature.2- amino methylpyrimidine acetate (0.48g, 2.8mmol) and triethylamine (2.8mmol) are dissolved in into dichloromethane first In, add dropwise in reactant liquor.Finish, react 1 hour, by 3- chloro- 4- methoxybenzylamine hydrochlorides (0.59g, 2.8mmol) Dropwise it is added drop-wise in above-mentioned reactant liquor with the mixed liquor of triethylamine (0.29g, 2.8mmol), reacts 2 hours after dripping, then to L- Prolinols (0.43g, 4.3mmol) are added in reactant liquor, room temperature reaction is overnight.Reactant liquor is poured in frozen water and is quenched, two Chloromethanes are extracted 2 times, are washed with water 2 times after merging organic faciess, and anhydrous sodium sulfate drying, the crude product Jing column chromatographies obtained after concentration are obtained White solid 0.9g, i.e. avanaphil, yield 64%.
1HNMR(DMSO-d6,400Hz):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 (22)

1. a kind of method of synthesis avanaphil, the preparation method is one of following method：
Method one：
5- uracil carboxylate (X) Jing halogenating reactions generate 2,4- dihalos -5- pyrimidine carboxylic esters (XI)；
There is substitution reaction in compounds X I and 3- chloro-4-methoxy benzylamines (II) or its salt, generate 2- halo -4- (the chloro- 4- first of 3- Epoxide benzamido group) -5- pyrimidine carboxylic esters (XII), which can be isolated and purified, and can not also separate and be directly used in next step；
Compounds X II and L- dried meat ammonia alcohol (VI) is further substituted with generating compound VII,
Avanaphil (I) obtained and ammonolysis reaction with 2- amino methylpyrimidines (IX) or its salt in compound VII there is；Or,
Compound VII is first hydrolyzed and is obtained sour (VIII), then is carried out amidation process with 2- amino methylpyrimidines (IX) or its salt and obtained To avanaphil (I),
Synthetic route is as shown in reaction equation 2：
Reaction equation 2：
Wherein,
Straight or branched alkyls of the R selected from C1～C6；
X is selected from halogen；
Method two：
5- uracil carboxylic acids (XIII) carries out amidation process or 5- uracil carboxylics with 2- amino methylpyrimidines (IX) or its salt Acid esters (X) carries out ammonolysis reaction and obtains compounds X IV with 2- amino methylpyrimidines (IX) or its salt；
Compounds X IV Jing halogenating reactions obtain halides XV；
Compounds X VI generated and substitution reaction with 3- chloro-4-methoxy benzylamines (II) or its salt in halides XV there is；
Compounds X VI and L- dried meat ammonia alcohol (VI) carries out substitution reaction and obtains avanaphil (I),
Synthetic route is as shown in reaction equation 3：
Reaction equation 3：
Wherein,
Straight or branched alkyls of the R selected from C1～C6；
X is selected from halogen；
Method three：
5- uracil carboxylic acids (XIII) Jing halos and carboxylic acid activated reacting generating compound XVII；
Compounds X VII carries out ammonolysis reaction with 2- amino methylpyrimidines (IX) or its salt and generates compounds X V；
Compounds X V and 3- chloro-4-methoxy benzylamines (II) or its salt are further substituted with generating compounds X VI；
Compounds X VI and L- dried meat ammonia alcohol (VI) carries out substitution reaction and obtains avanaphil (I),
Synthetic route is as shown in reaction equation 4：
Reaction equation 4：
Wherein, X is selected from halogen.
2. method according to claim 1, wherein,
In reaction equation 2, straight or branched alkyls of the R selected from C1～C4；And/or X is chlorine or bromine；And/or
In reaction equation 3, straight or branched alkyls of the R selected from C1～C4；X is chlorine or bromine；And/or
In reaction equation 4, X is chlorine or bromine.
3. method according to claim 1, wherein,
In reaction equation 2, R is methyl, ethyl or the tert-butyl group；And/or
In reaction equation 3, R is methyl, ethyl or the tert-butyl group.
4. the method according to any one of claim 1-3, wherein,
The substitution reaction is carried out in the presence of a base, wherein, the alkali is selected from inorganic base, organic base and its combination；And/or it is described The reaction dissolvent of substitution reaction is selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent and other solvents；Described other solvents Selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, N-Methyl pyrrolidone, hexamethyl phosphoramide, third Ketone, acetonitrile, ethyl acetate and its combination；And/or
The reaction temperature of the substitution reaction is -30 DEG C～300 DEG C；The response time of the substitution reaction is 1～12 hour.
5. method according to claim 4, wherein,
The inorganic base is selected from sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, calcium hydroxide, hydrogen-oxygen Change caesium, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate, sodium sulfide, sodium hydrogen and its combination；And/or
The organic base is selected from sodium alkoxide, potassium alcoholate, butyl lithium, 1,8- diazacyclos [5,4,0] hendecene -7, pyridine, piperidines, pyrroles Alkane, morpholine, N-methylmorpholine, quinoline, DMAP, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropyl Base amine, diisopropylethylamine and its combination；And/or
The aromatic hydrocarbon solvent is selected from benzene,toluene,xylene, chlorobenzene, Nitrobenzol and its combination；And/or
The ether solvent selected from tetrahydrofuran, ether, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether, two Six ring of oxygen and its combination；And/or
The halogenated hydrocarbon solvent is selected from dichloromethane, chloroform, carbon tetrachloride, dichloroethanes and its combination；And/or
The reaction temperature of the substitution reaction is -10 DEG C～150 DEG C.
6. method according to claim 4, wherein, the alkali is selected from sodium hydroxide, potassium hydroxide, Lithium hydrate, carbonic acid Hydrogen sodium, potassium bicarbonate, potassium carbonate, sodium carbonate, Feldalat NM, Sodium ethylate, potassium tert-butoxide, pyridine, piperidines, pyrrolidine, morpholine, N- first Base morpholine, triethylamine, diethylamine, diisopropylamine, diisopropylethylamine and its combination.
7. the method according to any one of claim 1-3, wherein,
Described hydrolysis are carried out in presence of an acid, and the acid is selected from organic acid, mineral acid or its combination；Or the hydrolysis Reaction is carried out in the presence of a base, and the alkali is selected from inorganic base, organic base and its combination；And/or
The solvent of the hydrolysis is selected from water, C1～C5Alcohol, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, diformazan Sulfoxide, tetrahydrofuran, acetonitrile, dioxane, morpholine, N-Methyl pyrrolidone, dichloromethane, chloroform, glycol dimethyl ether, two One or more in glycol dimethyl ether, glycol monoethyl ether；And/or
The reaction temperature of the hydrolysis is at -10 DEG C～300 DEG C；And/or
The response time of the hydrolysis is between 10 minutes～24 hours.
8. method according to claim 7, wherein,
The acid is one or more in sulphuric acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid；Or
The inorganic base is selected from sodium hydroxide, potassium hydroxide, Strontium hydrate., Lithium hydrate, barium hydroxide, calcium hydroxide, hydrogen-oxygen Change caesium, sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, strontium carbonate, cesium carbonate and its combination；
The organic base is selected from potassium acetate, sodium acetate, 1,8- diazacyclos [5,4,0] hendecene -7, pyridine, quinoline, 4- diformazans Aminopyridine, triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine and its combination；With/ Or
The solvent of the hydrolysis is one or more in water, methanol, ethanol, tetrahydrofuran, dioxane；With/ Or
The reaction temperature of the hydrolysis is between 0 DEG C～100 DEG C；And/or
The response time of the hydrolysis is between 0.5～10 hour.
9. method according to claim 7, wherein, the alkali is selected from sodium hydroxide, potassium hydroxide, Lithium hydrate, carbonic acid Potassium, sodium carbonate and its combination.
10. the method according to any one of claim 1-3, wherein,
Described halogenating reaction is carried out in the presence of halogenating agent；And/or
The halogenating reaction is carried out in the presence of with or without reaction dissolvent；And/or
The reaction temperature of the halogenating reaction is between -30 DEG C～300 DEG C.
11. methods according to claim 10, wherein,
The halogenating agent is in phosphorus oxychloride, phosphorus pentachloride, Phosphorous chloride., chlorine, bromine, iodine and tribromo oxygen phosphorus Plant or several；And/or
The reaction dissolvent of the halogenating reaction is selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, diformazan One or more in benzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；And/or
The reaction temperature of the halogenating reaction is between -5 DEG C～150 DEG C.
12. methods according to any one of claim 1-3, wherein, the halo and carboxylic acid activated reaction are tried in halo Carry out in the presence of agent；And/or
The halo and carboxylic acid activated reaction are carried out in the presence of with or without reaction dissolvent；And/or
The reaction temperature of described halo and carboxylic acid activated reaction is between -30 DEG C～300 DEG C.
13. methods according to claim 12, wherein,
The halogenating agent be selected from thionyl chloride, thionyl bromide, pivaloyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, three One or more in phosphorus chloride and tribromo oxygen phosphorus；And/or
The reaction dissolvent is preferably selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chloroform, dimethylbenzene, N, N- One or more in dimethylformamide, DMAC N,N' dimethyl acetamide；And/or
The reaction temperature of described halo and carboxylic acid activated reaction is between -5 DEG C～150 DEG C.
14. methods according to any one of claim 1-3, wherein, the ammonolysis reaction in the presence of with or without alkali, Carry out in solvent；And/or
The reaction temperature of the ammonolysis reaction is between -30 DEG C～150 DEG C；And/or
The response time of the ammonolysis reaction is between 10 minutes～24 hours.
15. methods according to claim 14, wherein,
The alkali be selected from pyridine, piperidines, pyrrolidine, morpholine, N-methylmorpholine, quinoline, DMAP, triethylamine, Diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, Feldalat NM, Sodium ethylate, potassium tert-butoxide, butyl Lithium, 1,8- diazacyclos [5,4,0] hendecene -7, N-methylmorpholine, quinoline, DMAP, sodium hydrogen, sodium hydroxide, One or more in potassium hydroxide, Lithium hydrate, sodium bicarbonate, potassium bicarbonate, sodium carbonate and potassium carbonate；And/or
The solvent of the ammonolysis reaction is selected from aromatic hydrocarbon solvent, ether solvent, halogenated hydrocarbon solvent, other solvents and its combination； Described other solvents are selected from methanol, ethanol, ethylene glycol, normal hexane, hexamethylene, N,N-dimethylformamide, N, N- dimethyl One or more in acetamide, dimethyl sulfoxide, N-Methyl pyrrolidone, acetone, acetonitrile, ethyl acetate；And/or
The reaction temperature of the ammonolysis reaction is between -10 DEG C～120 DEG C.
16. methods according to claim 15, wherein,
The aromatic hydrocarbon solvent is one or more in benzene,toluene,xylene etc.；
The ether solvent be selected from tetrahydrofuran, ether, glycol dimethyl ether, diethylene glycol dimethyl ether, glycol monoethyl ether, One or more in dioxane；
The halogenated hydrocarbon solvent is one or more in dichloromethane, chloroform, carbon tetrachloride, dichloroethanes.
17. methods according to any one of claim 1-3, wherein, described amidation process is carried out as follows：Having or In the presence of without catalyst, carboxylic acid halides is generated with halogenating agent reaction, then carry out ammonolysis reaction with amine；
The reaction for generating carboxylic acid halides is carried out in the presence of with or without reaction dissolvent.
18. methods according to claim 17, wherein,
The halogenating agent be selected from thionyl chloride, oxalyl chloride, thionyl bromide, phosphorus oxychloride, tribromo oxygen phosphorus, Phosphorous chloride., five One or more in phosphorus chloride, pivaloyl chloride；
Described catalyst is one or more in N,N-dimethylformamide, diethylaniline, dimethylaniline；
The reaction dissolvent of the reaction for generating carboxylic acid halides is selected from dichloromethane, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene, chlorine One or more in imitative, dimethylbenzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide；
The reaction temperature of the reaction for generating carboxylic acid halides is between -30 DEG C～300 DEG C.
19. methods according to claim 18, wherein, the reaction temperature of the reaction for generating carboxylic acid halides is -5 DEG C～100 Between DEG C
20. methods according to any one of claim 1-3, wherein, the amidation process is carried out as follows：Using condensation Agent, under with or without catalysts conditions, is carried out with or without in the presence of alkali.
21. methods according to claim 20, wherein,
The condensing agent is N'- dicyclohexylcarbodiimides, 1- ethyl -3- (3- dimethylamino-propyls) carbodiimide selected from N, Phosphinylidyne diimidazole, N, N'- DIC, O- BTA-N, N, N', N'- tetramethylurea Tetrafluoroboric acid ester, O- (7- azo BTAs)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, BTA-N, N, N', N'- tetramethylurea One or more in hexafluorophosphoric acid ester, BTA -1- bases epoxide three (dimethylamino) phosphorus hexafluorophosphate；
The catalyst is one or more in 1- hydroxyls-BTA, 4- dimethylamino pyridines；
The alkali is selected from triethylamine, diethylamine, tri-n-butylamine, tripropylamine, diisopropylamine, diisopropylethylamine, front three Amine, pyridine, 2,6- lutidines, DMAP, piperidines, pyrrolidine, quinoline, morpholine, N-methylmorpholine, N- ethyls Morpholine, diisopropylamine, diisopropylethylamine, 1,8- diazacyclos [5,4,0] hendecene -7 and 1,5- diazabicylos One or more in [4.3.0]-nonyl- 5- alkene；
Reaction dissolvent selected from benzene, dimethylbenzene, toluene, dichloromethane, chloroform, tetrahydrofuran, ether, propyl ether, 1,4- dioxane, N,N-dimethylformamide, N, N- diethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile, dimethyl sulfoxide and above-mentioned solvent Mixture；
Reaction temperature is between -20 DEG C～200 DEG C.
22. methods according to claim 21, wherein,
Reaction dissolvent is tetrahydrofuran, acetonitrile, dichloromethane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or diformazan Sulfoxide；
Reaction temperature is between -10 DEG C～100 DEG C.
CN201410653978.8A 2013-11-19 2014-11-17 Preparation method of avanafil Active CN104650045B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410653978.8A CN104650045B (en) 2013-11-19 2014-11-17 Preparation method of avanafil

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2013105857030 2013-11-19
CN201310585703 2013-11-19
CN201410653978.8A CN104650045B (en) 2013-11-19 2014-11-17 Preparation method of avanafil

Publications (2)

Publication Number Publication Date
CN104650045A CN104650045A (en) 2015-05-27
CN104650045B true CN104650045B (en) 2017-04-19

Family

ID=53241744

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410653978.8A Active CN104650045B (en) 2013-11-19 2014-11-17 Preparation method of avanafil

Country Status (1)

Country Link
CN (1) CN104650045B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104710411B (en) * 2015-03-13 2017-04-26 安润医药科技（苏州）有限公司 Synthesis method of avanafil
CN108299545B (en) * 2017-01-12 2021-07-02 复旦大学 Method for preparing Symplocin A and epimer thereof
CN109553607B (en) * 2017-09-25 2020-09-01 镇江圣安医药有限公司 Pyrimidine carboxamide derivatives, preparation method, composition, preparation and application thereof
CN108467360B (en) * 2018-06-22 2021-04-30 江苏美迪克化学品有限公司 Preparation method and intermediate of apatinib
CN109776505B (en) * 2019-03-14 2021-07-27 扬州市三药制药有限公司 Preparation method of avanafil

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584799A (en) * 1999-09-16 2012-07-18 田边三菱制药株式会社 Aromatic nitrogenous six-membered ring compounds
CN103254180A (en) * 2013-05-23 2013-08-21 苏州明锐医药科技有限公司 Preparation method of Avanafil
CN103254179A (en) * 2013-05-23 2013-08-21 苏州明锐医药科技有限公司 Preparation method of Avanafil
CN103265534A (en) * 2013-05-23 2013-08-28 苏州明锐医药科技有限公司 Method for preparing avanafil
CN103483323A (en) * 2013-08-23 2014-01-01 苏州永健生物医药有限公司 Avanafil
CN104059025A (en) * 2013-03-20 2014-09-24 广州朗圣药业有限公司 Novel intermediate used for preparation of avanafil and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584799A (en) * 1999-09-16 2012-07-18 田边三菱制药株式会社 Aromatic nitrogenous six-membered ring compounds
CN104059025A (en) * 2013-03-20 2014-09-24 广州朗圣药业有限公司 Novel intermediate used for preparation of avanafil and preparation method thereof
CN103254180A (en) * 2013-05-23 2013-08-21 苏州明锐医药科技有限公司 Preparation method of Avanafil
CN103254179A (en) * 2013-05-23 2013-08-21 苏州明锐医药科技有限公司 Preparation method of Avanafil
CN103265534A (en) * 2013-05-23 2013-08-28 苏州明锐医药科技有限公司 Method for preparing avanafil
CN103483323A (en) * 2013-08-23 2014-01-01 苏州永健生物医药有限公司 Avanafil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Synthesis and biological evaluation of 5-carbamoyl-2-phenylpyrimidine derivatives as novel and potent PDE4 inhibitors;Taiji Goto等;《Bioorganic & Medicinal Chemistry》;20130919;第21卷;第7027页反应式4化合物25-26 *

Also Published As

Publication number Publication date
CN104650045A (en) 2015-05-27

Similar Documents

Publication Publication Date Title
CN104650045B (en) Preparation method of avanafil
CN105859728B (en) A kind of preparation method that Buddhist nun is replaced according to Shandong
CN106946917B (en) A kind of JAK inhibitor Ba Rui replaces the novel synthesis of Buddhist nun and its intermediate
JP7377307B2 (en) Method for producing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one
CN111592467B (en) Nilaparib intermediate, preparation method and application thereof, and synthetic method of nilapab
TWI737763B (en) Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamides
CN103254179B (en) Preparation method of Avanafil
CN114478690B (en) Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane derivative
CN114805314A (en) Synthesis method of Ensaitevir
JP7405967B2 (en) Efficient method for preparing tedizolid intermediate and its intermediate
CN105153149B (en) A kind of selective kinase inhibitors Palbociclib preparation method
CN109867673B (en) Method for synthesizing palbociclib
JP6985179B2 (en) Method for producing proline amide compound
KR101143073B1 (en) Process for the synthesis of glyt-1 inhibitors
CN108239089B (en) Method for synthesizing avibactam sodium
CN107428718B (en) Preparation method of brexpiprazole analogue
WO2011156355A1 (en) Production method of phenyl guanidine salts and their intermediates
JP2024503855A (en) Method for synthesizing aminopyrimidine-based FAK inhibitor compounds
CN109020977B (en) Preparation method of Acaraburtinib
EA007497B1 (en) Improved method of making nevirapine
WO2023226900A1 (en) 2-(piperazine-2-yl) acetonitrile derivative, preparation method for, and use thereof
CN103421032B (en) A kind of bortezomib intermediate and its preparation method and application
CN103421033B (en) (1R) is prepared by one-method of (S)-pinine glycol-1 Amino 3 methyl butane-1-boric acid ester and salt thereof
CN112824381B (en) Preparation method of piperidine amine
CN111233857A (en) Synthetic method for continuously producing pexidartinib

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20181101

Address after: 215123 Suzhou 10 Suzhou building, Suzhou Industrial Park, D.

Patentee after: SUZHOU VIGONVITA LIFE SCIENCES Co.,Ltd.

Address before: 215123 Jiangsu 398 Suzhou Industrial Park, Suzhou

Co-patentee before: TOPHARMAN SHANGHAI Co.,Ltd.

Patentee before: SUZHOU VIGONVITA LIFE SCIENCES Co.,Ltd.

Co-patentee before: TOPHARMAN SHANDONG Co.,Ltd.

TR01 Transfer of patent right
CP03 Change of name, title or address

Address after: 215123 Floor 8, Building A, No. 108, Yuxin Road, Suzhou Industrial Park, Suzhou, China (Jiangsu) Pilot Free Trade Zone

Patentee after: Suzhou Wangshan Wangshui Biopharmaceutical Co.,Ltd.

Country or region after: China

Address before: 215123 Suzhou 10 Suzhou building, Suzhou Industrial Park, D.

Patentee before: SUZHOU VIGONVITA LIFE SCIENCES Co.,Ltd.

Country or region before: China

CP03 Change of name, title or address