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CN108129513A - A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate - Google Patents

A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate Download PDF

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Publication number
CN108129513A
CN108129513A CN201810104078.6A CN201810104078A CN108129513A CN 108129513 A CN108129513 A CN 108129513A CN 201810104078 A CN201810104078 A CN 201810104078A CN 108129513 A CN108129513 A CN 108129513A
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formula
compound
bouguer
reaction
buddhist nun
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吴学平
丁同俊
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Anqing Qi Chuang Pharmaceutical Co Ltd
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Anqing Qi Chuang Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a kind of methods for synthesizing Bouguer and replacing Buddhist nun's intermediate, include the following steps：(1) acylated condensation reaction under the action of metallic catalyst, acid binding agent is occurred into for compound of formula I and Formula II compound and obtains intermediate state formula III compound, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；(2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；(3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, is i.e. Bouguer replaces Buddhist nun's intermediate.The present invention provides new method for Bouguer for the structure of Buddhist nun's pyrimidine ring, the generation of competitive reaction is avoided, reduces the generation of by-product, while carries out reaction process cycle to the recycling of ammonium salt, route is easy to operate, reaction step is shortened, reaction condition is mild, good reaction selectivity, overall yield is higher, product liquid phase purity is high, considerably reduces production cost, is more advantageous to industrialized production.

Description

A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate.
Background technology
It is a kind of completely new oral anaplastic lymphoma kinase (anaplastic developed by Ariad companies that Bouguer, which replaces Buddhist nun, Lymphoma kinase, ALK) inhibitor, FDA listing approvals, trade name Alunbrig are obtained in April, 2017.For treating To gram azoles for Buddhist nun do not tolerate or medication after progression of disease patient treat anaplastic lymphoma kinase (ALK) positive metastatic it is non- Patients With Small Cell Carcinoma of The Lung, Bouguer replace Buddhist nun better than gram azoles to the selectivity of ALK for Buddhist nun, the G1202R of ALK can effectively be inhibited to be mutated. In addition, further include fibrosarcoma, diffusivity large B cell lymphoid tumor and primary cutaneous type etc. grinding indication.Thus It can be seen that Bouguer has good market prospects for Buddhist nun, and particularly important is just shown for the study on the synthesis of Buddhist nun to Bouguer.
Bouguer is entitled for the chemistry of Buddhist nun：The chloro- N2- of 5- [4- [(4- methylpiperazine-1-yls) piperidin-1-yl] -2- methoxybenzenes Base]-N4- [2- (dimethyl Asia phosphono) phenyl] -2,4- pyrimidinediamines, concrete structure is as follows：
Patent WO2009143389 reports the structure and synthetic method that Bouguer replaces Buddhist nun, document (J.Med.Chem.20 for the first time 16,59,4948-4964) and patent US2015225436, WO201665028 etc. also report its synthetic method.It is reported at present Be mainly intermediate A for the synthetic method of Buddhist nun about Bouguer and substitution reaction occurs for intermediate B, process is shown below：
Study on the synthesis at present about key intermediate A is more, (J.Med.Chem.2016,59,4948-4964) report A kind of preparation method of intermediate A is shown in route one.This method be by 2- Iodoanilines and dimethyl phosphine palladium/ Under Xantphos catalysis, with K3PO4For acid binding agent, coupling obtains (2- aminophenyls) dimethyl phosphine, then with 2,4,5- tri- Intermediate A (2- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) dimethyl phosphine is obtained by the reaction in chlorine pyrimidine.This method exists The problem of be：The chlorine of 2 and 4 during 2,4,5- trichloropyrimidines and (2- aminophenyls) dimethyl phosphine replace There are competitive reactions, lead to selective reduction；The building-up process of intermediate A reacts incomplete, post-processes purifying complex, yield not Height, two-step reaction total recovery are only 49.9%；Operating process is complicated, is unfavorable for industrialized production.
CN107522742A discloses a kind of homogeneous " one kettle way " preparation method of intermediate A, and this method is with by route one One pot of three kinds of raw materials feed intake and reacted, although yield slightly improves compared with route one, 2 in the synthesis process Chlorine with 4 still has very big competitive reaction, and raw material availability is caused to reduce.Chinese journal of Medicinal Chemistry reports one simultaneously Kind is shown in route two about the optimum synthesis method of intermediate A, although this method uses Pd (PPh3)2Cl2As catalyst instead of The palladium of document report and Xantphos dual catalysts, but competitive reaction is equally existed, and in intermediate A and intermediate B has used microwave heating, but this process is unfavorable for the production of industrial-scale during reacting.
To sum up, Bouguer in the synthesis of Buddhist nun there are low yield, synthesis is complicated, raw material availability is low, of high cost and be unfavorable for The problems such as industrialization generation, and pyrimidine ring is only resided within to the research of intermediate A and is reacted with the participation of other raw materials, no The competitive reaction of pyrimidine ring substituents is avoided that, so there is still a need for find simpler, efficient novel synthesis.
Invention content
Goal of the invention：Bouguer is prepared at present for product yield in the method for Buddhist nun is low, building-up process is complicated and gives birth in order to overcome The defects of of high cost is produced, the present invention provides one kind there is industrialization potential and high income, by-product to recycle, product purity Method high, synthesis step is few, simple synthesis Bouguer replaces Buddhist nun's intermediate.
Technical solution：The method that synthesis Bouguer of the present invention replaces Buddhist nun's intermediate, includes the following steps：
(1) acylated condensation reaction is occurred under the action of metallic catalyst, acid binding agent for compound of formula I and Formula II compound Intermediate state formula III compound is obtained, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；
(2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；
(3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, is i.e. Bouguer replaces Buddhist nun Intermediate；
Wherein, R is selected from the linear or branched alkyl group of C1-C4, preferably methyl, ethyl, propyl, butyl, more preferable ethyl；X1 Selected from F, Cl, Br, I, preferably Cl.
In step (1), the molar ratio of compound of formula I and Formula II compound is (2-4): 1, preferably (2.5-3.5): 1.
In step (1), the metallic catalyst is aluminium chloride, one kind in iron chloride, copper chloride, palladium bichloride, palladium Or several, preferred aluminium chloride；The molar ratio of Formula II compound and metallic catalyst is 1: (0.1-0.4), preferably 1: 0.2； The acid binding agent is sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N- One or more of dimethylamino naphthyridine, N- methyl piperidines, N- methyl beautiful jades, preferably triethylamine；Formula II compound is with tiing up acid The molar ratio of agent is 1: (0.2-1.5), preferably 1: 0.5.
In step (1), the solvent used in acylated condensation reaction is ethyl alcohol, dichloroethanes, dichloromethane, dimethylacetamide One or more of amine, dimethyl sulfoxide (DMSO), tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, acetonitrile or toluene, preferably dichloromethane；Instead It is 60~110 DEG C to answer temperature, preferably 60~90 DEG C, most preferably 65~80 DEG C.
In step (1), acid hydrolysis reaction acid used is hydrochloric acid, sulfuric acid, phosphoric acid, one kind in trifluoroacetic acid or several Kind, preferably hydrochloric acid；Wherein, a concentration of 37wt% of hydrochloric acid；A concentration of 98wt% of sulfuric acid, phosphoric acid concentration 85wt%；Formula II The molar ratio of compound and acid is 1: (1-2), preferably 1: 1.2.
In step (1), ammonium salt IV further adds alkali to generate raw material compound of formula I, recycles.The ammonium salt IV adds alkali The alkali that generation compound of formula I is used is sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, hydrogen-oxygen Change one or more of potassium, calcium hydroxide, magnesium hydroxide, barium hydroxide, preferably sodium carbonate；The throwing of IV compound of ammonium salt and alkali It is 1 to expect molar ratio: (1-3), preferably 1: 1.5.
In step (2), the molar ratio of Formula V compound and urea is 1: (1-3), preferably 1: (1.25-2.5), it is optimal Select 1: 1.5.
In step (2), reaction dissolvent is methanol, ethyl alcohol, n,N-Dimethylformamide, dimethylacetylamide, dimethyl are sub- One or more of sulfone, toluene, dichloromethane, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, acetonitrile, preferably N, N- dimethyl formyls Amine；Reaction temperature is 65~95 DEG C, preferably 80 DEG C.
In step (3), nucleopilic reagent is one or more of halogen acids, phosphorus Halides, thionyl chloride, and halogen acids is hydrogen chlorine One or more of acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, phosphorus Halides for phosphorus tribromide, phosphorus trichloride, phosphorus triiodide one Kind is several.The preferred thionyl chloride of nucleopilic reagent.The molar ratio of Formula VII compound and nucleopilic reagent is 1: (1-3), preferably 1: (1.2-2), most preferably 1: 1.2.
In step (3), reaction temperature is 0~90 DEG C, preferably 60~85 DEG C.
A kind of method for synthesizing Bouguer and replacing Buddhist nun, the step of including above-mentioned VIII compound of formula, further including will be described Formula VIII compound occurs substitution reaction with Formula IX compound and obtains Formula X compound, i.e. Bouguer replaces Buddhist nun,
The Formula VIII compound is 1 with Formula IX compound molar ratio: (1-2), preferably 1: (1.2-1.5)；Substitution There is acid to participate in reaction in reaction, acid used is one or more of hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, preferably trifluoro The molar ratio of acetic acid, VIII compound of formula and acid is 1: (0.2-1.5), preferably 1: 0.5.Reaction dissolvent is methanol, ethyl alcohol, third Alcohol, isopropanol, n-butanol, the tert-butyl alcohol, dimethylformamide, dimethylacetylamide, dimethyl sulfoxide (DMSO), toluene, dichloromethane, four One or more of hydrogen furans, Isosorbide-5-Nitrae-dioxane, acetonitrile, preferred alcohol.Reaction temperature is 50~100 DEG C, preferably 70-90 ℃。
The synthetic route of the present invention is as follows：
Wherein, R is selected from the linear or branched alkyl group of C1-C4, X1Selected from F, Cl, Br, I.
Preferably, synthesis Bouguer of the present invention includes the following steps for the method for Buddhist nun：
By compound of formula I 2- (dimethyl phosphoroso-) aniline and -1 compound of Formula II (chloroformyl) ethyl acetate in metal Acylated condensation reaction occurs under the action of catalyst and obtains intermediate state formula III, acid adding carries out that Formula V compound 2- is obtained by the reaction later Chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides and ammonium salt IV, water phase ammonium salt add alkali to generate starting materials of formulae I chemical combination Object recycles；
Condensation reaction is occurred into for the Formula V compound and urea VI and obtains Formula VII compound (2- ((5- chlorine-2-hydroxyls Pyrimidine-4-yl) amino) phenyl) dimethyl phosphine；
Substitution reaction is occurred into for the Formula VII compound and nucleopilic reagent thionyl chloride and obtains -1 compound 2 of Formula VIII, Bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine；
By -1 compound of Formula VIII and Formula IX compound 2- methoxyl groups -4- [4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases] aniline occurs substitution reaction and obtains Formula X compound, i.e., and Bouguer replaces Buddhist nun,
Advantageous effect：Present invention synthesis Bouguer replaces the method for Buddhist nun, and relative to the prior art, the structure for pyrimidine ring provides New method is avoided using noble metal catalyst or strong reductant reagent etc., realizes that the recycling of by-product, raw material utilizes Rate is high, reaction condition is mild, and synthesis step is few, and good reaction selectivity, overall yield is higher, and product liquid phase purity is high, drops significantly Low production cost, is more suitable for industrialized production.
Specific embodiment
Embodiment 1
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
2- (dimethyl phosphoroso-) aniline (I) (21.12.4g, 125mmol), (chloroformyl) second are added in reaction bulb Acetoacetic ester (II-1) (7.5g, 50mmol), aluminium chloride (1.333g, 10mmol) do catalyst, triethylamine (0.253g, 2.5mmol) do acid binding agent, dichloromethane (150mL) be solvent, be stirred to react 16h at 80 DEG C.TLC detection reactions are completed.Reaction Terminate addition 5.8ml hydrochloric acid (concentration 37wt%) and be stirred to react 3h, make intermediate state III that reaction be hydrolyzed, 30ml is added after hydrolysis Water makes reaction liquid layer, and aqueous phase solution makes ammonium salt be converted into raw material 2- (dimethyl by adding in sodium carbonate (7.9g, 75mmol) Phosphoroso-) aniline (I).Organic phase after wherein hydrolyzing is washed 2 times with saturated common salt, and anhydrous sodium sulfate drying is evaporated under reduced pressure back Solvent is received, gained concentrate ethyl acetate and n-hexane (1: 1, V/V) recrystallize to obtain compound 2- chloro- N- (2- (dimethyl Phosphono) phenyl) -3- oxopropanamides (V) 11.2g；Yield 82%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
Intermediate 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) are added in reaction bulb (10.9g, 40mmol), urea (VI) (3.6g, 50mmol), n,N-Dimethylformamide (100mL) are solvent, are stirred at 80 DEG C Mix reaction 12h.TLC detection reactions are completed.Reaction terminates plus reaction is quenched in water 150mL, and organic phase is washed 2 times with saturated common salt, Water phase is extracted with ethyl acetate 2 times, merges organic phase, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, gained concentrate use Petroleum ether and ethyl acetate mixed solvent column chromatography for separation obtain compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) benzene Base) dimethyl phosphine (VII) 9.758g；Yield 85%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：m/ Z=298.05 (M+H).
Bis- chloro- N- of (3) 2,5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos Base) phenyl) -3- oxopropanamides (VIII -1) preparation
Intermediate (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine is added in reaction bulb (VII) (10.4g, 35mmol) and nucleopilic reagent thionyl chloride (5g, 42mmol), 10h is stirred to react at 85 DEG C.TLC detections are anti- It should complete.Reaction terminates plus reaction is quenched in water 150mL, and organic phase is washed 2 times with saturated common salt, and water phase is extracted with ethyl acetate 2 It is secondary, merge organic phase, anhydrous sodium sulfate drying, vacuum distillation recovered solvent, gained concentrate ethyl acetate and n-hexane (1: 1, V/V) compound 2, bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2- are recrystallized to obtain (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII -1) 10.25g；Yield 93%；(return for 99.9% by HPLC areas for purity One method)；Mass spectrum (ESI)：M/z=313.98 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
Intermediate 2 is added in reaction bulb, bis- chloro- N- of 5- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- is chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII -1) (9.45g, 30mmol), 2- methoxyl groups -4- [4- (4- Methylpiperazine-1-yl) piperidin-1-yl] aniline (IX) (11g, 36mmol), trifluoroacetic acid (1.7g, 15mmol), ethyl alcohol (100mL) is solvent, and 12h, condenser pipe reflux are stirred to react at 90 DEG C.TLC detection reactions are completed.Reaction terminates plus water 150mL Reaction is quenched, organic phase is washed 2 times with saturated common salt, and water phase is extracted with ethyl acetate 2 times, merges organic phase, anhydrous sodium sulfate Dry, vacuum distillation recovered solvent, gained concentrate is recrystallized with n-hexane, and vacuum drying obtains white solid product cloth Lattice replace Buddhist nun (X) 16.1g；Yield 92%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=584.26 (M+ H)。
Embodiment 2
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：Raw material compound of formula I and the molar ratio of -1 compound of Formula II are 3.5: 1, acylated condensation alkali used is pyridine, and solvent is toluene, and reaction temperature is 65 DEG C, and it is phosphoric acid (concentration to hydrolyze the acid used 85wt%).
Palladium bichloride (1.77g, 10mmol) is catalyst, the final gained chloro- N- of compound 2- (2- (dimethyl phosphine acyl group) Phenyl) -3- oxopropanamides (V) 11.33g；Yield 83%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)： M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 2.5, and solvent is toluene, Reaction temperature is 95 DEG C.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII) 9.5g；Yield 80%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the bromo- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos Base) phenyl) -3- oxopropanamides (VIII-2) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is hydrobromic acid, and VII compound of formula and feeding intake for nucleopilic reagent are rubbed , than being 1: 2, reaction temperature is 60 DEG C for you.
The final gained bromo- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-2) 9.37g；Yield 85%；Purity is 99.5% (HPLC areas Normalization method)；Mass spectrum (ESI)：M/z=357.86 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 2 compound of Formula VIII is 1: 2 with Formula IX compound molar ratio, Dimethyl sulfoxide (DMSO) is solvent, and used acid is hydrochloric acid, and reaction temperature is 70 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) 14.87g；Yield 85%；Purity is 99.8% (HPLC areas Normalization method)；Mass spectrum (ESI)：M/z=584.26 (M+H).
Embodiment 3
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：(chloroformyl) ethyl acetate (II-1) replaces with (chloroformyl) acetic acid first Ester (II-2).The molar ratio of raw material compound of formula I and -2 compound of Formula II is 2: 1.Palladium bichloride is catalyst, and Formula II -2 is changed The molar ratio for closing object and catalyst is 1: 0.1.It is acylated to be condensed alkali used as sodium methoxide, the throwing of -2 compound of Formula II and alkali It is 1: 0.2 to expect molar ratio.Acylated condensation reaction dissolvent used is ethyl alcohol, and reaction temperature is 60 DEG C.Acid adding water after acylated condensation The acid that solution is used is trifluoroacetic acid, and -2 compound of Formula II is 1: 1 with sour molar ratio.
Final gained compound 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) yield 81%； Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 1, and solvent is tetrahydrochysene furan It mutters, reaction temperature is 65 DEG C.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII) 9.5g；Yield 81%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the fluoro- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos Base) phenyl) -3- oxopropanamides (VIII-3) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is hydrofluoric acid, and VII compound of formula and feeding intake for nucleopilic reagent are rubbed , than being 1: 1, reaction temperature is 0 DEG C for you.
The final gained fluoro- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-3) yield 83%；Purity is 99.5% (HPLC area normalizations Method)；Mass spectrum (ESI)：M/z=298.12 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 3 compound of Formula VIII is 1: 1 with Formula IX compound molar ratio, Dichloromethane is solvent, and used acid is sulfuric acid, and reaction temperature is 50 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) yield 83%；Purity is 99.8% (HPLC area normalization methods)； Mass spectrum (ESI)：M/z=584.26 (M+H).
Embodiment 4
(1) preparation of the chloro- N- of 2- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V)
With embodiment 1, the difference lies in：(chloroformyl) ethyl acetate (II-1) replaces with (chloroformyl) acetic acid third Ester (II-3).The molar ratio of raw material compound of formula I and -3 compound of Formula II is 4: 1.Palladium is catalyst, Formula II -3 The molar ratio of compound and catalyst is 1: 0.4.Acylated condensation alkali used is potassium tert-butoxide, -3 compound of Formula II and alkali Molar ratio be 1: 0.5.Acylated condensation reaction dissolvent used is tetrahydrofuran, and reaction temperature is 110 DEG C.Acylated contracting The acid that acid hydrolysis is used after conjunction is sulfuric acid (concentration 98wt%), and -3 compound of Formula II is 1: 2 with sour molar ratio.
Final gained compound 2- chloro- N- (2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (V) 11.33g；It receives Rate 81.5%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=274.04 (M+H).
(2) preparation of (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII)
With embodiment 1, the difference lies in：The molar ratio of Formula V compound and urea is 1: 3, and solvent is ethyl alcohol, instead It is 80 DEG C to answer temperature.
Final gained compound (2- ((5- chlorine-2-hydroxyls pyrimidine-4-yl) amino) phenyl) dimethyl phosphine (VII) is received Rate 82%；Purity is 99.8% (HPLC area normalization methods)；Mass spectrum (ESI)：M/z=298.05 (M+H).
(3) the chloro- N- of the iodo- 5- of 2- (2- (dimethyl Asia phosphono) phenyl) pyrimidine -4- amine 2- chloro- N- (2- (dimethyl phosphonos Base) phenyl) -3- oxopropanamides (VIII-4) preparation
With embodiment 1, the difference lies in：Nucleopilic reagent is phosphorus triiodide, and VII compound of formula and nucleopilic reagent feed intake Molar ratio is 1: 3, and reaction temperature is 90 DEG C.
The final gained iodo- 5- of compound 2- chloro- N- (2- (dimethyl Asia phosphono) phenyl) chloro- N- (2- of pyrimidine -4- amine 2- (dimethyl phosphine acyl group) phenyl) -3- oxopropanamides (VIII-4) 9.37g；Yield 82%；Purity is 99.5% (HPLC areas Normalization method)；Mass spectrum (ESI)：M/z=405.47 (M-H).
(4) Bouguer replaces the preparation of Buddhist nun (X)
With embodiment 1, the difference lies in：- 4 compound of Formula VIII is 1 with Formula IX compound molar ratio: 1.5, tetrahydrofuran is solvent, and used acid is hydrochloric acid, and reaction temperature is 100 DEG C.
Final gained white solid product Bouguer replaces Buddhist nun (X) yield 83%；Purity is 99.8% (HPLC area normalization methods)； Mass spectrum (ESI)：M/z=584.26 (M+H).

Claims (10)

  1. A kind of 1. method for synthesizing Bouguer and replacing Buddhist nun's intermediate, which is characterized in that include the following steps：
    (1) compound of formula I acylated condensation reaction occur under the action of metallic catalyst, acid binding agent with Formula II compound to obtain Intermediate state formula III compound, acid adding, which is hydrolyzed, later is obtained by the reaction Formula V compound and ammonium salt IV；
    (2) condensation reaction is occurred into for the Formula V compound and urea and obtains VII compound of formula；
    (3) substitution reaction is occurred into for VII compound of formula and nucleopilic reagent and obtains VIII compound of formula, i.e., Bouguer is among Buddhist nun Body,
    Wherein, R is selected from the linear or branched alkyl group of C1-C4；X1Selected from F, Cl, Br, I.
  2. 2. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), Formulas I The molar ratio for closing object and Formula II compound is (2-4): 1.
  3. 3. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), the gold Metal catalyst is one or more of aluminium chloride, iron chloride, copper chloride, palladium bichloride, palladium；Formula II compound is urged with metal The molar ratio of agent is 1: (0.1-0.4)；The acid binding agent for sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, Triethylamine, diisopropyl ethyl amine, pyridine, N, one kind or several in N- dimethylamino naphthyridines, N- methyl piperidines, N- methyl beautiful jades Kind, the molar ratio of Formula II compound and acid binding agent is 1: (0.2-1.5).
  4. 4. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), acylated contracting Close reaction solvent used be ethyl alcohol, dichloroethanes, dichloromethane, dimethylacetylamide, dimethyl sulfoxide (DMSO), tetrahydrofuran, 1, One or more of 4- dioxane, acetonitrile or toluene；Reaction temperature is 60~110 DEG C.
  5. 5. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), acid adding water Solution reaction acid used is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid；Formula II compound is rubbed with feeding intake for acid You are than being 1: (1-2).
  6. 6. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (1), ammonium salt IV Further plus alkali generates compound of formula I.
  7. 7. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (2), Formula V The molar ratio for closing object and urea is 1: (1-3).
  8. 8. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (2), reaction is molten Agent is methanol, ethyl alcohol, n,N-Dimethylformamide, dimethylacetylamide, dimethyl sulfoxide (DMSO), toluene, dichloromethane, tetrahydrochysene furan It mutters, one or more of Isosorbide-5-Nitrae-dioxane, acetonitrile；Reaction temperature is 65~95 DEG C.
  9. 9. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (3), nucleophilic examination Agent is one or more of halogen acids, phosphorus Halides, thionyl chloride, and the molar ratio of Formula VII compound and nucleopilic reagent is 1 ∶(1-3)。
  10. 10. the method that synthesis Bouguer according to claim 1 replaces Buddhist nun's intermediate, which is characterized in that in step (3), reaction Temperature is 0~90 DEG C.
CN201810104078.6A 2018-02-01 2018-02-01 A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate Pending CN108129513A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
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WO2019148789A1 (en) * 2018-02-02 2019-08-08 苏州科睿思制药有限公司 Crystal form of ap26113 and preparation method therefor
CN112047978A (en) * 2019-06-05 2020-12-08 北京赛思源生物医药技术有限公司 Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine
CN112239422A (en) * 2020-10-16 2021-01-19 河北化工医药职业技术学院 Bugatinib intermediate, salt thereof, preparation method thereof and preparation method of brigatinib
CN112675175A (en) * 2021-02-01 2021-04-20 天津济坤医药科技有限公司 Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522742A (en) * 2017-10-20 2017-12-29 常州工程职业技术学院 A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107522742A (en) * 2017-10-20 2017-12-29 常州工程职业技术学院 A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019148789A1 (en) * 2018-02-02 2019-08-08 苏州科睿思制药有限公司 Crystal form of ap26113 and preparation method therefor
CN112047978A (en) * 2019-06-05 2020-12-08 北京赛思源生物医药技术有限公司 Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine
CN112239422A (en) * 2020-10-16 2021-01-19 河北化工医药职业技术学院 Bugatinib intermediate, salt thereof, preparation method thereof and preparation method of brigatinib
CN112675175A (en) * 2021-02-01 2021-04-20 天津济坤医药科技有限公司 Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis
CN112675175B (en) * 2021-02-01 2022-11-01 天津济坤医药科技有限公司 Application of brigatinib in preparation of medicine for treating idiopathic pulmonary fibrosis

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Application publication date: 20180608