CN108456183A - The preparation method and intermediate of Gedatolisib - Google Patents

The preparation method and intermediate of Gedatolisib Download PDF

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CN108456183A
CN108456183A CN201810194841.9A CN201810194841A CN108456183A CN 108456183 A CN108456183 A CN 108456183A CN 201810194841 A CN201810194841 A CN 201810194841A CN 108456183 A CN108456183 A CN 108456183A
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compound
phenyl
dimethylamino
triazine
formula
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韩冠宇
朱国庆
沈尧
杨瑞
王星妍
茆勇军
王晗
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Shanghai University of Engineering Science
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Shanghai University of Engineering Science
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the preparation fields of organic synthesis and bulk pharmaceutical chemicals intermediate, and in particular to the preparation method of the preparation method of Gedatolisib, key intermediate and key intermediate.4 (4,6 dimorpholino, 1,3,5 triazine, 2 base) aniline are made through s-triazine cyclization, the cyclization of morpholine ring, nitro hydro-reduction in p-nitrophenyl nitrile and dicyanodiamine；Noval chemical compound (4 aminophenyl) (4 (dimethylamino) piperidinyl-1 base) ketone is made through addition, de- Boc protecting groups, amidation, nitro hydro-reduction in 4 oxo-piperidine, 1 t-butyl formate and dimethylamine salt；Using one kettle way, (4,6 dimorpholinos 1,3,5 triazine, 2 base) after aniline reacts with phenyl chloroformate, (4 aminophenyl) (4 (dimethylamino) piperidinyl-1 base) ketone is added, Gedatolisib is finally made.The preparation method have many advantages, such as raw material be easy to get, concise in technology, easy to operate, high income and at low cost.

Description

The preparation method and intermediate of Gedatolisib
Technical field
The invention belongs to the preparing technical field of organic synthesis and bulk pharmaceutical chemicals intermediate, more particularly to a kind of anti-cancer drugs The preparation method and intermediate of Gedatolisib.
Background technology
Gedatolisib (research and development codes：PF-05212384,PKI-587；Molecular formula：C32H41N9O4；No. CAS： 1197160-78-3；Structural formula is shown in formula I), chemical name is 1- (4- (4- (dimethylamino) piperidines -1- carbonyls) benzene Base) -3- (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) urea is highly effective pair of the one kind researched and developed by Pfizer Weight PI3K α, PI3K γ and mTOR inhibitors are now in clinical three phases, while the chemical combination for treating acute myelogenous leukemia Object is in clinical I phase for treating solid tumor.
Formulas I：1- (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- (4- (4,6- dimorpholinos -1,3,5- three Piperazine -2- bases) phenyl) urea (Gedatolisib)；Formula II：4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline；Formula III： (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone.
Currently, the preparation method of document report Gedatolisib is as shown in Scheme 1, it is with 2,4,6- tri- chloro- 1,3,5- Triazine (1) is used as starting material, by the substitution of morpholine ring, phenyl ring be coupled to obtain key intermediate 4- (4,6- dimorpholinos -1,3, 5- triazine -2- bases) aniline (II)；Then by synthesizing compound 1- (4- acetylphenyls) -3- (4- with isocyanates with aniline (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) urea (3), then by finally being produced after ester hydrolysis, amide reaction Product (J Med.Chem., 2010,53 (6), 2636-2645；WO2010096619；WO2009143317).
The reaction condition and yield of 1 each step of route are a：Triethylamine (Et3N), acetone/water (Acetone/H2O), -10 DEG C, 16h, 64%；b：Tetrakis triphenylphosphine palladium (Pd (PPh3)4), dimethylformamide (DMF), sodium carbonate (Na2CO3), reflux (reflux), 5h, 88%；c：Dichloromethane (DCM), room temperature (rt), 5h, 90%；d:Lithium hydroxide (LiOH), tetrahydrofuran (THF), methanol (MeOH), room temperature (rt), H2O, 3h, 92%；e：O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU), N-Methyl pyrrolidone (NMP), room temperature (rt), 16h, 50%.
Route 1
On the whole apparently, which is chain type synthetic method, and this adduction synthetic method makes product yield very It is low.In synthetic route, 2,4,6- tri- chloro-1,3,5-triazines of raw material, (4,4,5,5- tetramethyls -1,3, the 2- dioxas that use Ring pentaborane -2- bases) aniline, 1- (4- isocyanatophenyls) second -1- ketone and N, N- lupetidine -4- amine comparing on the market Costly；The first step is relatively low using the reaction yield of chlorine atom on morpholine substitution s-triazine, and second step uses (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) aniline is coupled, and need DMF to be carried out under 150 DEG C of counterflow conditions, and made Tetrakis triphenylphosphine palladium is heavy metal catalyst, be easy to cause heavy-metal residual；Final step carboxylic acid and secondary amine on piperidines Amidation process, be catalyzed using n,N-diisopropylethylamine, at the same for ensure compound 4 dissolubility, N- need to be used Methyl pyrrolidone is as solvent.
As can be seen that the synthesis cost of former process route is relatively high, at the synthetic method of simultaneously synthesizing product and purifying Reason has many defects, limits ability prepared by its amplification.Therefore, it is necessary to for the defect in the presence of the prior art, to existing There is technology to be improved, provide a kind of raw material be easy to get, concise in technology, easy to operate, the higher preparation method of yield, with reduce at This amplifies potentiality with industry is made it have.
Invention content
The present invention is directed in view of the drawbacks of the prior art, provide a kind of preparation method of Gedatolisib, the preparation method Have many advantages, such as raw material be easy to get, concise in technology, easy to operate, high income and at low cost.
The present invention also provides the preparation methods of the related intermediate for preparing Gedatolisib and related intermediate.
Preparing for Gedatolisib of the present invention is as shown in Scheme 2：
Route 2
As shown in Scheme 2, compound 1- (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- of Formulas I is synthesized The new intermediate of (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) urea is the compound phenyl (4- (4,6- of formula 16 Dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate or formula III compound (4- aminophenyls) (4- (diformazans Base amino) piperidin-1-yl) ketone.
Compound phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate of the formula 16 Preparation method it is as shown in Scheme 2, step includes：In organic solvent, compound 4- (4,6- dimorpholinos -1,3, the 5- of Formula II Triazine -2- bases) after aniline mixes with phenyl chloroformate under the conditions of 0 DEG C~5 DEG C, under room temperature, catalyst action substitution reaction give birth to Compound phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate of an accepted way of doing sth 16.
The molar concentration of 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline is 0.15~1mol/L, preferably 0.15~0.5mol/L；The molar ratio of 4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline and phenyl chloroformate is 1： 0.9~1.5, preferably 1：1；The molar ratio of 4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline and catalyst is 1：2 ~5, preferably 1：2.3~4.
The organic solvent includes dimethylformamide, acetonitrile, dimethyl sulfoxide (DMSO), acetone or N-Methyl pyrrolidone etc., Preferably dimethylformamide；The catalyst includes pyridine, triethylamine, 4-dimethylaminopyridine or diisopropylethylamine etc., Preferably pyridine.
Route 3
Compound (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone of the formula III it is a kind of new Preparation method is as shown in Scheme 3, and step includes：
(a) in the organic solvent containing acid, under catalyst action, the compound 4- oxo-piperidine -1- t-butyl formates of formula 9 With compound 4- (dimethylamino) piperidines -1- t-butyl formates of dimethylamine hydrochloride through reductive amination process production 10；
(b) in hydrochloric organic solvent, compound 4- (dimethylamino) piperidines -1- t-butyl formates of formula 10 are de- The compound N of Boc protecting groups production 11, N- lupetidine -4- amine hydrochlorates；
(c) in organic solvent, the compound N of formula 11, N- lupetidine -4- amine hydrochlorates and 4- nitrobenzoyl chlorides are anti- Answer compound (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt of production 12；
(d) in organic solvent, under hydrogen and catalysts conditions, compound (4- (dimethylamino) piperidines -1- of formula 12 Base) compound (the 4- aminophenyls) (4- (diformazans of (4- nitrobenzophenones) methanone hvdrochloric acid salt through catalytic hydrogen reduction production III Base amino) piperidin-1-yl) ketone；
Or in the aqueous containing acid alcohol of reducing metal-, compound (4- (dimethylamino) piperidin-1-yl) (4- of formula 12 Nitrobenzophenone) compound (4- aminophenyl) (4- (dimethylamino) piperidines -1- of the methanone hvdrochloric acid salt through reduction production III Base) ketone.
In step (a), the molar concentration of 4- oxo-piperidine -1- t-butyl formates is 0.8~1.5mol/L, preferably 1mol/L；The molar ratio of 4- oxo-piperidine -1- t-butyl formates and dimethylamine hydrochloride is 1：1~5, preferably 1：1.5~3, More preferably 1：2；The molar ratio of 4- oxo-piperidine -1- t-butyl formates and acid is 1：1.5~2.5, preferably 1：1.7~2；4- The molar ratio of oxo-piperidine -1- t-butyl formates and catalyst is 1：0.8~1.5, preferably 1：1.
In step (a), the organic solvent includes methanol, ethyl alcohol, isopropanol or tetrahydrofuran, preferably methanol；It is described Acid is organic acid or inorganic acid, and organic acid includes acetic acid, formic acid or trifluoroacetic acid etc., and inorganic acid includes hydrochloric acid, sulfuric acid or hydrogen bromine Acid etc., preferably acetic acid；The catalyst is borohydride catalyst, including sodium borohydride, sodium cyanoborohydride or three second Triacetoxyborohydride, preferably sodium cyanoborohydride.
In step (a), reaction temperature is 0 DEG C~room temperature, preferably 0~10 DEG C, more preferably 5 DEG C；The time of reaction is 10~40 hours, preferably 10~20 hours.
Step (a) after reaction, after reaction solution concentration, after adding lye pH adjustment=11 or so, adds dichloromethane extraction It takes, for gained organic phase after saturated common salt water washing, dehydration and drying obtains pale yellow oily liquid object 4- (dimethylamino) piperazine Pyridine -1- t-butyl formates.
Organic examination is added specifically, 4- (dimethylamino) piperidines -1- t-butyl formates are dissolved in organic solvent A in step (b) The mixed solution of agent B and hydrochloric acid take off the compound N of Boc protecting groups production 11, N- lupetidine -4- amine hydrochlorates.It is organic Solvent A and B are identical or different solvent.The organic chemical A includes dichloromethane, ethyl acetate, chloroform or ether etc., Preferably dichloromethane or dioxane.The organic reagent B includes dioxane, ethyl acetate, ether, tetrahydrofuran or two Chloromethanes etc., preferably dioxane.
In step (b) reaction system, the molar concentration of 4- (dimethylamino) piperidines -1- t-butyl formates is 0.4 × 10-3 ~1 × 10-3Mol/L, preferably 0.45 × 10-3~0.5 × 10-3mol/L；4- (dimethylamino) piperidines -1- t-butyl formates Molar ratio with hydrochloric acid is 1：2.5~3.5, preferably 1：3.
In step (b), reaction temperature is 0 DEG C~room temperature, preferably 0~10 DEG C, more preferably 5 DEG C；Reaction time be 5~ 10 hours.
In step (c), the molar concentration of N, N- lupetidine -4- amine hydrochlorates are 0.5~1.5mol/L, preferably 0.5~0.8mol/L；The molar ratio of N, N- lupetidine -4- amine hydrochlorates and 4- nitrobenzoyl chlorides is 1：0.9~1.5, Preferably 1：1.
In step (c), the organic solvent includes toluene, dichloromethane, chlorobenzene or ethyl acetate etc., preferably toluene or Dichloromethane.
Step (c) reaction temperature is room temperature, and the reaction time is 8~20 hours.
In the organic solvent of step (d), (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt Molar concentration is 0.15~0.8mol/L, preferably 0.15~0.5mol/L, more preferably 0.2mol/L；(4- (dimethylaminos Base) piperidin-1-yl) molar ratio of (4- nitrobenzophenones) methanone hvdrochloric acid salt and catalyst is 1：5~10, preferably 1：8.5~9.
The catalyst of step (d) is metallic catalyst, metal oxide catalyst or metal sulfide catalyst, and metal is urged Agent includes nickel, Raney's nickel, platinum or palladium etc., preferably nickel；Metal oxide catalyst includes copper oxide-copper chromite or oxidation Aluminium-zinc oxide-chromium oxide etc., metal sulfide catalyst include nickel-molybdenum sulfide etc..
The organic solvent of step (d) is tetrahydrofuran, methanol, ethyl alcohol or isopropanol etc., preferably tetrahydrofuran.
In the aqueous containing acid alcohol of step (d), (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt Molar concentration be 0.4~1mol/L, preferably 0.4~0.6mol/L, more preferably 0.43mol/L；(4- (dimethylamino) Piperidin-1-yl) molar ratio of (4- nitrobenzophenones) methanone hvdrochloric acid salt and reducing metal is 1：3~4, preferably 1：3~3.5；(4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt with acid molar ratio be 1：3~6, preferably 1：3.4 ~4.The acid includes hydrochloric acid, sulfuric acid or hydrobromic acid etc., preferably hydrochloric acid.The reducing metal includes iron, zinc, tin, magnesium or aluminium Deng preferably iron or zinc.
In the aqueous containing acid alcohol of step (d), the volume ratio of alcohol and water is 1：0.8~1, preferably 1：1；Alcohol include methanol, Ethyl alcohol or isopropanol etc., preferably ethyl alcohol.
Step (d), under the conditions of atmosphere of hydrogen, organic solvent, the temperature of hydrogenation reduction is room temperature, and the time is 5~20 Hour；Hydrogenation reduction under the conditions of the aqueous containing acid alcohol of reducing metal-carries out at a reflux temperature, and the time is 5~15 hours.
Route 4
1- (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- (4- (4,6- dimorpholino -1,3,5- triazines - 2- yls) phenyl) urea (Gedatolisib) preparation method, as shown in Scheme 4, step includes：In organic solvent or generate In the reaction solution of phenyl (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) carbamate, the compound benzene of formula 16 The compound (4- aminophenyls) of base (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate and formula III Compound 1- (4- (4- (dimethylamino) piperidines-of (4- (dimethylamino) piperidin-1-yl) ketone substitution reaction production I 1- carbonyls) phenyl) -3- (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) urea.
The present invention uses one kettle way, in compound phenyl (4- (4, the 6- dimorpholinos -1,3,5-triazines -2- of production 16 Base) phenyl) carbamate reaction solution in, carry out phenyl (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) ammonia Substitution reaction between carbamate and compound (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone of formula III, Optimum synthesis step reduces catalysts and solvents dosage, cost-effective.
In organic solvent or generate phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamic acid In the reaction solution of ester, the molar concentration of (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone is 0.1~ 0.5mol/L, preferably 0.13~0.2mol/L；(4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone and phenyl The molar ratio of (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate is 1：0.8~1.5, preferably 1： 1。
The organic solvent includes dimethylformamide, acetonitrile, dimethylacetylamide or glycol monoethyl ether, preferably Dimethylformamide.
The temperature of the substitution reaction is 85 DEG C~120 DEG C, preferably 90 DEG C；The time of substitution reaction is 5~15 hours, Preferably 5~10 hours.
After above-mentioned substitution reaction, reaction solution is added in ice water, the solid phase 1- (4- (4- (dimethylaminos of precipitation are stirred Base) piperidines -1- carbonyls) phenyl) -3- (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) urea, then it is pure through column chromatography Change, column chromatography mobile phase is dichloromethane：Methanol：Methanol ammonia=10:1:0.2.
Route 5
The present invention also provides the one of the compound 4- of the Formula II (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline The new preparation method of kind, as shown in Scheme 5, step includes：
(1) under alkaline condition, in organic solvent, compound p-nitrophenyl nitrile and the dicyanodiamine ring-closure reaction of formula 5 generate Compound (4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines of formula 6；
(2) under the inorganic salts strong alkali environment of inert gas shielding or under organic base environment, in organic solvent, the change of formula 6 Close object (4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines and the chloro- 2- of 1- (2- chloroethoxies) ethane ring closure reactions production 7 Compound 4,4'- (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine；
(3) under hydrogen and catalysts conditions, in organic solvent, the compound 4 of formula 7,4'- (6- (4- nitrobenzophenones) -1,3, 5- triazine -2,4- diyls) dimorpholine hydrogenating reduction production II compound 4- (4,6- dimorpholino -1,3,5- triazines -2- Base) aniline.
In step (1), the molar concentration of p-nitrophenyl nitrile is 1~2mol/L, preferably 1.2~1.5mol/L；To nitro The molar ratio of cyanophenyl and dicyanodiamine is 1：1~2, preferably 1：1~1.5, more preferably 1：1；P-nitrophenyl nitrile and alkali rub You are than being 1：0.15~0.5, preferably 1：0.15~0.2.
In step (1), the organic solvent includes ethylene glycol monomethyl ether, acetonitrile, DMF or dioxane etc., preferably second two Alcohol methyl ether.
In step (1), the temperature of ring-closure reaction is 80 DEG C~110 DEG C, preferably 90 DEG C；The time of ring-closure reaction be 2~ 10 hours, preferably 5 hours.
After step (1) ring-closure reaction, reaction solution is cooled to room temperature, washed filtering, obtains white powdery solid (4- nitre Base phenyl) -1,3,5- triazine -2,4- diamines.
In step (2), the molar concentration of (4- nitrobenzophenones) -1,3,5-triazines -2,4- diamines is 0.2~0.5mol/L, Preferably 0.25mol/L；(4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines rubs with the chloro- 2- of 1- (2- chloroethoxies) ethane You are than being 1：1~5, preferably 1：3~5, more preferably 1：4；(4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines with it is inorganic The molar ratio of salt highly basic is 1：5~12, preferably 1：7~10, more preferably 1：9~9.5；(4- nitrobenzophenones) -1,3,5- three The molar ratio of piperazine -2,4- diamines and organic base is 1：2~20, preferably 1：2~5, preferably 1：3.
In step (2), the inorganic salts highly basic includes sodium hydride, lithium hydride, hydrofining, rubidium hydride or cesium hydride, preferably For lithium hydride；The organic base includes triethylamine, pyridine, DMAP or morpholine, preferably triethylamine；The inert gas includes argon Gas or nitrogen, preferably argon gas.
In step (2), the temperature of ring closure reaction is 50 DEG C~80 DEG C, preferably 55 DEG C~60 DEG C；The time of ring closure reaction It is 1~10 hour, preferably 4~8 hours.
As a preferred solution of the present invention, the inorganic salts strong alkali environment or organic base environment of inert gas shielding Under, in organic solvent, the compound (4- nitrobenzophenones) of formula 6-1,3,5-triazines-2,4- diamines first with inorganic salts highly basic or have Machine alkali reacts, then the compound 4 with the chloro- 2- of 1- (2- chloroethoxies) the ethane ring closure reactions production 7 of addition, 4'- (6- (4- Nitrobenzophenone) -1,3,5- triazine -2,4- diyls) dimorpholine.(4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines and inorganic salts The time of highly basic or organic base reaction is 8~15 minutes, preferably 10 minutes.Using sodium hydride etc. as the reaction condition of alkali Be conducive to improve yield, reduce reaction gas generating rate, improves safety.
After step (2) ring closure reaction, reaction solution is added in ice water, light brown solid 4,4'- (6- (4- is precipitated in stirring Nitrobenzophenone) -1,3,5- triazine -2,4- diyls) dimorpholine.
In step (3), the molar concentration of 4,4'- (6- (4- nitrobenzophenones) -1,3,5-triazines -2,4- diyl) dimorpholines is 0.04~0.1mol/L, preferably 0.047mol/L；4,4'- (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) two The molar ratio of quinoline and catalyst is 1：3~6, preferably 1：3.5~4.
In step (3), the organic solvent includes tetrahydrofuran, methanol, ethyl alcohol, isopropanol or dioxane etc., preferably For tetrahydrofuran；The catalyst is metallic catalyst, metal oxide catalyst or metal sulfide catalyst, metal catalytic Agent includes nickel, Raney's nickel, platinum or palladium etc., preferably nickel；Metal oxide catalyst includes copper oxide-copper chromite or oxidation Aluminium-zinc oxide-chromium oxide etc., metal sulfide catalyst include nickel-molybdenum sulfide etc..
The temperature of step (3) hydrogenation reduction is room temperature, and the time of hydrogenation reduction is 5~20 hours.
After step (3) hydrogenation reduction, reaction solution is filtered with diatomite, is concentrated to give orange solids 4- (4,6- bis- Morpholino -1,3,5- triazine -2- bases) aniline.
This method using p-nitrophenyl nitrile, dicyanodiamine, 4- oxo-piperidine -1- t-butyl formates and dimethylamine salt as raw material, Key intermediate 4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline and (4- aminophenyls) (4- (dimethyl of synthesis Amino) piperidin-1-yl) ketone, target compound 1- (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl)-is finally made 3- (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) phenyl) urea (Gedatolisib), compared with the existing technology, the present invention The advantages of synthetic route, is：
(1) present invention is with more typical p-nitrophenyl nitrile, dicyanodiamine, 4- oxo-piperidine -1- t-butyl formates and diformazan Amine salt is starting material, and the reaction condition of each step of synthetic route is mild, post-processing is easy to be easily-controllable, is suitble to amplification to prepare, and each Step high income.
(2) present invention provides the key intermediate 4- (4,6- dimorpholino -1,3,5- triazines -2- of synthesis Gedatolisib Base) aniline a kind of novel synthesis, the synthetic method is using p-nitrophenyl nitrile and dicyanodiamine as starting material, through s-triazine ring Conjunction, the cyclization of morpholine ring, nitro hydro-reduction.
(3) present invention provides key intermediate (4- aminophenyls) (4- (dimethylamino) piperazine of synthesis Gedatolisib Pyridine -1- bases) ketone a kind of novel synthesis, which is with 4- oxo-piperidine -1- t-butyl formates and dimethylamine salt Starting material, through addition, de- Boc protecting groups, amidation, nitro hydro-reduction.
(4) raw material of synthetic route of the present invention is simple and easy to get, and each step need not introduce excessive blocking group, atom warp Ji property is good, and the reaction condition of each step is mildly easily-controllable, reduces cost.
Specific implementation mode
Technical scheme of the present invention is illustrated below in conjunction with specific embodiment.
The preparation of embodiment 1 (4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines
1.25g potassium hydroxide (22mmol) is dissolved in 100mL ethylene glycol monomethyl ethers, and 12.5g dicyan two is then added thereto again Amine (0.15mol) and 17.75g p-nitrophenyls nitrile (0.12mol) are mixed, and are heated to 90 DEG C of reaction 4h.
It after the reaction was complete, is cooled to room temperature, the white pureed solid of filtering gained washs filtering with water (15 × 2mL), obtains white Color powdery solid 24.3g.Yield is 82.2%.
1H NMR (400MHz, DMSO-d6)：δ 6.92 (s, 4H), 8.40 (dd, J=44.3,8.8Hz, 4H)
The preparation of 2 4,4'- of embodiment (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine
9.0g 60%NaH (0.23mol) are dissolved in 75mL DMAC (dimethylacetylamide) under protection of argon gas；Opening is stirred It mixes, then control temperature adds 5.8g (4- nitrobenzophenones) -1,3,5-triazines -2,4- diamines to 55 DEG C~60 DEG C After ten minutes, then the chloro- 2- of 14.2g 1- (2- chloroethoxies) ethane for being dissolved in 25mL DMAC is added dropwise in (25mmol), reaction (0.1mol) reacts 4.5h.
After the reaction was complete, ice water (500mL) crystallization of 5 times of amounts, stirring are added into the reaction solution being cooled to room temperature 25min filters, obtains light brown solid 8.8g, yield 94.6%.
1H NMR (400MHz, CDCl3-d6)：3.78 (t, 8H), 3.95 (m, 8H), 6.57 (d, J=8.5Hz, 2H), 8.05 (d, J=8.5Hz, 2H) .ESI-MS (m/z) 372.3 [M+H]+
The preparation of 3 4,4'- of embodiment (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine
7g NaH (0.175mol, 60%) are dissolved in 75mL DMAC under protection of argon gas；Open stirring, control temperature to 55 DEG C~60 DEG C, 5.8g (4- nitrobenzophenones) -1,3,5-triazines -2,4- diamines (25mmol) is then added, about 15min is added, 15min is reacted again；The chloro- 2- of 10.7g 1- (2- chloroethoxies) ethane (0.075mol) for being dissolved in 20mL DMAC is finally added dropwise, about 15min is added, then reacts 8h.
After the reaction was complete, ice water (500mL) crystallization of 5 times of amounts, stirring are poured into the reaction solution being cooled to room temperature 25min filters, obtains light brown solid 8.8g.Yield 50.6%.
Spectrogram testing result is the same as embodiment 2.
The preparation of 4 4,4'- of embodiment (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine
0.3g Et3N triethylamines (3mmol) are added in 5mL DMAC；Stirring is opened, 60 DEG C is warming up to, then adds After stirring 10min, the chloro- 2- (2- of 0.426g1- are added dropwise in 0.23g (4- nitrobenzophenones) -1,3,5-triazines -2,4- diamines (1mmol) Chloroethoxy) ethane (3mmol), reacts 8h.
After the reaction was complete, the reaction solution that will be cooled to room temperature pours into 25mL ice water, stirs 25min, filters, obtains pale yellow Solid 0.1g.Yield 26.89%.
Spectrogram testing result is the same as embodiment 2.
The preparation of 5 4- of embodiment (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline
5.17g 4,4'- (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine (0.014mol) is dissolved in In 300mL THF, the 3.0g Ni (51mmol) of wash clean are added, after replacing hydrogen, be passed through hydrogen, 20h is stirred at room temperature.
After the reaction was complete, reaction solution adds diatomite to filter, and filtrate is concentrated to dryness, and obtains orange solids, and weigh 4.63g.It receives Rate 96.6%.
1H NMR (400MHz, CDCl3-d6)：δ 3.64 (s, 8H), 3.78 (s, 8H), 5.70 (s, 2H), 6.57 (d, J= 8.5Hz, 2H), 8.05 (d, J=8.4Hz, 2H) .ESI-MS (m/z) 343.0 [M+H]+.
The preparation of embodiment 6 4- (dimethylamino) piperidines -1- t-butyl formates
10g 4- oxo-piperidine -1- t-butyl formates (0.05mol) are dissolved in 50mL methanol, 8.15g dimethylamine is added Hydrochloride (0.10mol) adds 5mL glacial acetic acid (0.087mol), is finally placed in ice-water bath.After temperature drops to 5 DEG C 3.25g Na (CN) BH is added portionwise3(0.052mol) reacts 16h.
After the reaction was complete, it is concentrated under reduced pressure, obtains pureed solid, add NaOH (4g)/H2O (30mL) solution tune pH=11 is left Then the right side is extracted, saturated common salt water washing with 150 × 2mL DCM (dichloromethane), after anhydrous sodium sulfate drying, be concentrated and dried Final products are obtained, are a pale yellow oily liquid 10.41g.Yield is 91.31%.
1H NMR (400MHz, D2O-d6)：δ1.38(m,1H).1.46(s,9H),1.83(m,2H),2.28(s,6H), 2.71(m,2H),4.13–3.59(m,2H).
The preparation of embodiment 7 N, N- lupetidine -4- amine hydrochlorates
10.0g 4- (dimethylamino) piperidines -1- t-butyl formates (0.044mol) are dissolved in 60mL dichloromethane, are set In ice bath, then the HCl/ dioxane solutions (34.5mL, 0.138mol) of 4mol/L are added dropwise, 8h is mixed.
After the reaction was complete, there are a large amount of white solids to be precipitated, filtering is washed with a small amount of cold dichloromethane, in vacuum decompression item HCl is removed under part.Finally obtain product 6.4g.Yield is 85.3%.
1H NMR (400MHz, D2O-d6)：δ 1.99-1.87 (m, 2H) .2.33 (d, J=13.6Hz, 2H), 2.85 (s, 6H), 3.05 (d, J=13.3Hz, 1H), 3.66-3.50 (m, 3H)
The preparation of embodiment 8 (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt
By 3.5g 4- nitrobenzoyl chlorides (0.019mol) and 3.58g N, N- lupetidine -4- amine hydrochlorates (17.8mmol) is dissolved in 35mL toluene, stirring at normal temperature 18h.
After the reaction was complete, the total 2.0g of solid product is filtered to obtain.Yield 36.3%.
1H NMR (400MHz, CDCl3-d6)：δ1.45(m,2H),1.57(m,2H),1.83(m,2H),2.00(m,2H), 2.45 (s, 6H), 2.90 (t, 2H), 3.08 (t, 2H), 3.67 (d, J=11.4Hz, 2H), 4.73 (d, J=10.7Hz, 2H), 7.58 (d, J=8.7Hz, 2H), 8.30 (d, J=8.7Hz, 2H)
The preparation of embodiment 9 (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone
1.2g (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt (3.8mmol) is dissolved in In 20mL THF, the 2.0g Ni (34mmol) of wash clean are added, after replacing hydrogen, be passed through hydrogen, 20h is stirred at room temperature.
After the reaction was complete, reaction solution adds diatomite to filter, and filtrate is concentrated to dryness, and obtains white solid, and weigh 0.95g.It receives Rate 88.7%.
1H NMR (400MHz, CDCl3-d6)：δ1.62–1.38(m,2H),2.01–1.73(m,2H),2.35(s,6H), 2.49 (m, 1H), 2.89 (m, 2H), 3.85 (s, 2H), 4.34 (s, 2H), 6.65 (d, J=8.5Hz, 2H), 7.25 (d, J= 8.5Hz,2H).ESI-MS(m/z)248.1[M+H]+.
The preparation of embodiment 10 (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone
0.9g Fe powder (16.1mmol) is added to H2After O/ ethyl alcohol (5ml/5ml), 1.37mL hydrochloric acid is added dropwise After (16.5mmol), 10min is stirred, 1.53g (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) ketone is added portionwise Hydrochloride (4.89mmol), is heated to reflux, and stirs 6h.
After the reaction was complete, reaction solution adds diatomite to filter, and filtrate is concentrated to dryness, and obtains white solid, and weigh 0.95g.It receives Rate 88.7%.
Spectrogram testing result is the same as embodiment 10.
The preparation of 11 phenyl of embodiment (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate
1.71g 4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline (5mmol) is dissolved in 7mL DMF (dimethyl Formamide) in, 1.58g pyridines (20mmol) are added, are placed in ice bath, wait for that temperature is less than 5 DEG C, dropwise addition is dissolved in 3mL DMF's 0.86g phenyl chloroformates (5.5mmol) after being added dropwise to complete, are placed in room temperature reaction 2h.
After the reaction was complete, 50mL ice water will be poured into reaction solution, there are a large amount of solids to be precipitated, stir 20min, filter, obtain Solid 2.1g, yield 90%.
1H NMR(400MHz,CDCl3-d6)：δ3.83–3.75(m,8H).3.94(s,8H),7.25–7.12(m,3H), 7.43 (t, J=7.9Hz, 2H), 7.55 (d, J=8.6Hz, 2H), 8.40 (d, J=8.7Hz, 2H) .ESI-MS (m/z) 462.51 [M+H]+。
12 1- of embodiment (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- (4- (dimorpholino -1 4,6-, 3,5- triazine -2- bases) phenyl) urea preparation
By 0.46g phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate (0.99mmol) It is dissolved in 5mL DMF, heats with 0.24g (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone (0.97mmol) To 90 DEG C of reaction 12h.
After the reaction was complete, reaction solution is poured into 25mL water, a large amount of solids are precipitated, and stir 20min, filter, obtain solid 0.4g.Purifying uses column chromatography, mobile phase DCM：Methanol：Methanolic ammonia solution=10:1:0.2, solid 0.1g is finally obtained, is received Rate 16.3%.
1H NMR (400MHz, CDCl3-d6)：1.46(s,2H),1.89(s,2H),2.29(s,6H),2.38-2.46(m, 1H), 2.94 (s, 2H), 3.47 (s, 2H), 3.76 (t, 8H), 3.89 (s, 8H), 7.09 (d, J=8.4Hz, 2H), 7.20 (d, J =8.4Hz, 2H), 7.50 (d, J=8.7Hz, 2H), 8.28 (s, 1H), 8.31 (d, J=8.6Hz, 2H), δ 8.48 (s, 1H) .ESI-MS(m/z)615.9[M+H]+
13 1- of embodiment (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- (4- (dimorpholino -1 4,6-, 3,5- triazine -2- bases) phenyl) urea preparation
0.43g 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline (1.26mmol) is dissolved in 5mL DMF, 0.23g pyridines (3mmol) are added, are placed in ice bath, waits for that temperature is less than 5 DEG C, the 0.18g chloro-carbonic acid benzene for being dissolved in 3mLDMF is added dropwise Ester (1.15mmol).After being added dropwise to complete, it is placed in room temperature reaction.After reaction, 0.27g (4- aminophenyls) (4- (diformazans are added Base amino) piperidin-1-yl) ketone (1.1mmol), 90 DEG C are warming up to, 12h is reacted.
After the reaction was complete, reaction solution is poured into 50mL water, a large amount of solids are precipitated, and stir 20min, filter, obtain solid 0.2g.Purifying uses column chromatography, mobile phase DCM：Methanol：Methanolic ammonia solution=10:1:0.2, solid 0.11g is finally obtained, Yield 17.8%.
Spectrogram testing result is the same as embodiment 12.
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, it is ripe its object is to allow The personage for knowing this Project Technical cans understand the content of the present invention and implement it accordingly, and the protection model of the present invention can not be limited with this It encloses.Any equivalent change or modification in accordance with the spirit of the invention should be covered by the protection scope of the present invention.

Claims (10)

1. synthesizing the intermediate of Gedatolisib, which is characterized in that
For compound phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate or formula of formula 16 Compound (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone of III.
2. the preparation method of intermediate described in claim 1, which is characterized in that compound phenyl (4- (4, the 6- dimorpholines of formula 16 Generation -1,3,5- triazine -2- bases) phenyl) preparation method of carbamate includes the following steps：
In organic solvent, compound 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline and the phenyl chloroformate of Formula II exist After being mixed under the conditions of 0 DEG C~5 DEG C, substitution reaction generation phenyl (4- (4,6- dimorpholinos -1,3,5- under room temperature, catalyst action Triazine -2- bases) phenyl) carbamate.
3. the preparation method of intermediate described in claim 2, which is characterized in that 4- (4,6- dimorpholinos -1,3,5-triazines -2- Base) aniline molar concentration be 0.15~1mol/L, 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline and chloro-carbonic acid The molar ratio of phenyl ester is 1：The molar ratio of 0.9~1.5,4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline and catalyst It is 1：2~5.
4. the preparation method of intermediate described in claim 1, which is characterized in that compound (4- aminophenyls) (4- of formula III (dimethylamino) piperidin-1-yl) preparation method of ketone includes the following steps：
(a) in the organic solvent containing acid, under catalyst action, the compound 4- oxo-piperidine -1- t-butyl formates of formula 9 and two Compound 4- (dimethylamino) piperidines -1- t-butyl formates of methylamine hydrochloride through reductive amination process production 10；
(b) in hydrochloric organic solvent, compound 4- (dimethylamino) piperidines -1- t-butyl formates of formula 10 take off Boc The compound N of protecting group production 11, N- lupetidine -4- amine hydrochlorates；
(c) in organic solvent, the compound N of formula 11, N- lupetidine -4- amine hydrochlorates react life with 4- nitrobenzoyl chlorides Compound (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt of an accepted way of doing sth 12；
(d) in organic solvent, under hydrogen and catalysts conditions, compound (4- (dimethylamino) piperidin-1-yl) (4- of formula 12 Nitrobenzophenone) compound (4- the aminophenyls) (4- (dimethylamino) of methanone hvdrochloric acid salt through catalytic hydrogen reduction production III Piperidin-1-yl) ketone；
Or under the conditions of the aqueous containing acid alcohol of reducing metal-, compound (4- (dimethylamino) piperidin-1-yl) (4- of formula 12 Nitrobenzophenone) compound (4- aminophenyl) (4- (dimethylamino) piperidines -1- of the methanone hvdrochloric acid salt through reduction production III Base) ketone.
5. the preparation method of intermediate described in claim 4, which is characterized in that in step (a), 4- oxo-piperidine -1- formic acid uncles The molar concentration of butyl ester is 1.5~2mol/L, and the molar ratio of 4- oxo-piperidine -1- t-butyl formates and dimethylamine hydrochloride is 1： The molar ratio of 1~5,4- oxo-piperidine -1- t-butyl formates and acid is 1：1.5~2.5,4- oxo-piperidine -1- t-butyl formates Molar ratio with catalyst is 1：0.8~1.5；
In step (b) reaction system, the molar concentration of 4- (dimethylamino) piperidines -1- t-butyl formates is 0.4 × 10-3~1 ×10-3The molar ratio of mol/L, 4- (dimethylamino) piperidines -1- t-butyl formates and hydrochloric acid is 1：2.5~3.5；
In step (c), the molar concentration of N, N- lupetidine -4- amine hydrochlorates are 0.5~1.5mol/L, N, N- dimethyl piperazines The molar ratio of pyridine -4- amine hydrochlorates and 4- nitrobenzoyl chlorides is 1：0.9~1.5；
In the organic solvent of step (d), mole of (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt A concentration of 0.15~0.8mol/L, (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt and catalyst Molar ratio be 1：5~10；
In the aqueous containing acid alcohol of step (d), (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt rubs You are a concentration of 0.4~1mol/L, (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt and reducing metal Molar ratio be 1：3~4, the molar ratio of (4- (dimethylamino) piperidin-1-yl) (4- nitrobenzophenones) methanone hvdrochloric acid salt and acid It is 1：3~6.
The preparation method of 6.Gedatolisib, which is characterized in that step includes：
In organic solvent or the compound phenyl of production 16 (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) benzene Base) carbamate reaction solution in, compound phenyl (4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) benzene of formula 16 Base) carbamate and formula III compound (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone substitution reaction Production I compound 1- (4- (4- (dimethylamino) piperidines -1- carbonyls) phenyl) -3- (4- (dimorpholino -1,3 4,6-, 5- triazine -2- bases) phenyl) urea.
7. preparation method according to claim 6, which is characterized in that (4- aminophenyls) (4- (dimethylamino) piperidines- 1- yls) ketone molar concentration be 0.1~0.5mol/L, (4- aminophenyls) (4- (dimethylamino) piperidin-1-yl) ketone Molar ratio with phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamate is 1：0.8~1.5.
8. preparation method according to claim 6, which is characterized in that the compound phenyl (4- (4,6- bis- of the formula 16 Quinoline generation -1,3,5-triazines -2- bases) phenyl) carbamate preparation method, step includes：In organic solvent, the chemical combination of Formula II After object 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline is mixed with phenyl chloroformate under the conditions of 0 DEG C~5 DEG C, room Substitution reaction generates phenyl (4- (4,6- dimorpholino -1,3,5- triazine -2- bases) phenyl) carbamic acid under temperature, catalyst action Ester.
9. the preparation method of 4- (4,6- dimorpholinos -1,3,5-triazines -2- bases) aniline of Formula II structure, which is characterized in that step Suddenly include：
(1) under alkaline condition, the compound p-nitrophenyl nitrile of formula 5 and compound (the 4- nitre of dicyanodiamine ring-closure reaction production 6 Base phenyl) -1,3,5- triazine -2,4- diamines；
(2) under the inorganic salts strong alkali environment of inert gas shielding or under organic base environment, in organic solvent, the compound of formula 6 The change of (4- nitrobenzophenones) -1,3,5- triazine -2,4- diamines and the chloro- 2- of 1- (2- chloroethoxies) ethane ring closure reactions production 7 Close object 4,4'- (6- (4- nitrobenzophenones) -1,3,5- triazine -2,4- diyls) dimorpholine；
(3) under hydrogen and catalysts conditions, in organic solvent, the compound 4 of formula 7,4'- (6- (4- nitrobenzophenones) -1,3,5- tri- Piperazine -2,4- diyls) dimorpholine hydrogenating reduction production II structures 4- (4,6- dimorpholino -1,3,5- triazine -2- bases) aniline.
10. preparation method according to claim 9, which is characterized in that in step (1), the molar concentration of p-nitrophenyl nitrile For 1~2mol/L, the molar ratio of p-nitrophenyl nitrile and dicyanodiamine is 1：1~2, the molar ratio of p-nitrophenyl nitrile and alkali is 1： 0.15~0.5；
In step (2), the molar concentration of (4- nitrobenzophenones) -1,3,5-triazines -2,4- diamines is 0.2~0.5mol/L, (4- nitre Base phenyl) molar ratio of -1,3,5- triazine -2,4- diamines and the chloro- 2- of 1- (2- chloroethoxies) ethane is 1：1~5, (4- nitros Phenyl) molar ratio of -1,3,5- triazine -2,4- diamines and inorganic salts highly basic is 1：5~12, (4- nitrobenzophenones) -1,3,5- tri- The molar ratio of piperazine -2,4- diamines and organic base is 1：2~20；
In step (3), the molar concentration of 4,4'- (6- (4- nitrobenzophenones) -1,3,5-triazines -2,4- diyl) dimorpholines is 0.04 The molar ratio of~0.1mol/L, 4,4'- (6- (4- nitrobenzophenones) -1,3,5-triazines -2,4- diyl) dimorpholines and catalyst is 1：3~6.
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