CN109438441A - It is a kind of dimension how the preparation method and products thereof of appropriate drawing - Google Patents

It is a kind of dimension how the preparation method and products thereof of appropriate drawing Download PDF

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CN109438441A
CN109438441A CN201811450340.9A CN201811450340A CN109438441A CN 109438441 A CN109438441 A CN 109438441A CN 201811450340 A CN201811450340 A CN 201811450340A CN 109438441 A CN109438441 A CN 109438441A
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base
nitro
chlorphenyl
methyl
piperazine
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彭磊
黄雄鸠
何伟
唐丽昌
柳玲
陈振明
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Chongqing Sansheng Industry Ltd By Share Ltd
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Chongqing Sansheng Industry Ltd By Share Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

It is a kind of dimension how the preparation method of appropriate drawing, by 2- (1H- pyrrolo- [2, 3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4, 4- dimethyleyelohexane -1- alkenyl) methyl) piperazine -1- base) benzoic acid and 3- nitro -4- fluorobenzenesulfonamide/3- nitro -4- chlorobenzene sulfonamide be dissolved in solvent, by condensation reaction, isolated 4- (4- { [2- (4- chlorphenyl) -4, 4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorine (or chlorine) phenyl) sulfonyl)] -2- (1H- pyrrolo- [2, 3-b] pyridine -5- base oxygroup) benzamide；4- (4- { [2- (4- chlorphenyl) -4; 4- dimethyleyelohexane -1- alkene -1- base] methyl piperazine -1- base)-N- [(3- nitro -4- fluorine (or chlorine) phenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide again with oxinane -4- methylamine by substitution reaction, separate, be refining to obtain dimension how appropriate drawing.

Description

It is a kind of dimension how the preparation method and products thereof of appropriate drawing
Technical field
The present invention relates to field of medicaments, in particular to a kind of dimension how the preparation method and products thereof of appropriate drawing.
Background technique
Dimension how chemical entitled 4- (4- { [2- (4- the chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine of appropriate drawings Piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide is the selective depression of the first targeting B cell lymphoma factor 2 (BCL-2) Medicine.It is raw that the B cell lymphoma factor 2 (B-celllymphoma-2, BCL-2) in leukaemic's cell can promote cancer cell It is long, it is often over-expressed in bone-marrow-derived lymphocyte and other B cell malignant tumours, is ratified to list by FDA on April 11st, 2016, used In chronic lymphocytic leukemia.
How appropriate drawing is many at the route of report for dimension, but in existing technology, each synthetic route can all obtain identical Intermediate 2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- Alkenyl) methyl) piperazine -1- base) benzoic acid, directly with 3- nitro -4- ((tetrahydro -2H- pyrans -4- base) methylamino) benzene sulfonyl Amine by condensation reaction obtain tieing up how appropriate drawing.Synthetic route is as follows:
However, the defect of this synthesis mode is: 3- nitro -4- ((tetrahydro -2H- pyrans -4- base) methylamino) benzene sulphur There are two amino in amide, sulfonamide is and fragrant since the electron attraction of sulfonyl causes the amino activity in sulphonyl ammonia to reduce Although fragrant amine is that secondary amine has certain three-dimensional effect, but still has certain activity, aromatic amine can react production when condensation reaction By-product:
Lead to target product yield reduction and impurity content is more, isolate and purify difficulty, needing repeatedly to refine could be made The product to conform to quality requirements increases enterprise's production cost.Therefore, a kind of new how appropriate drawing Preparation Method of dimension is needed.
Summary of the invention
In view of the deficiencies of the prior art, it is an object of the present invention to provide it is a kind of dimension how the preparation method of appropriate drawing, technique item Part is mild, operation is convenient, simple, is suitable for industrialization large-scale production.The how appropriate drawing of dimension obtained using preparation method of the present invention Purity reaches 99.5% or more, and single impurity is less than 0.1%.
The synthesis equation of preparation method of the present invention is as follows:
The technical scheme is that it is a kind of dimension how the preparation method of appropriate drawing, it is described dimension how it is appropriate draw be 4- (4- { [2- (4- Chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans - 4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (I), it uses Following steps are made:
1) by 2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyl Hexamethylene -1- alkenyl) methyl) piperazine -1- base) benzoic acid (II), 4-dimethylaminopyridine and 3- nitro -4- fluorobenzenesulfonamide/3- Nitro -4- chlorobenzene sulfonamide is dissolved in solvent, and condensing agent is added and activator carries out condensation reaction, after completion of the reaction, separates, is pure Change obtains 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitre Base -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorine Phenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) sulfonyl)] - 2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III)；
2) by 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine-obtained by step 1) 1- yl)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/ 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorine Phenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III) and oxinane -4- methylamine It is dissolved in solvent, acid binding agent is added and carries out substitution reaction, separated after completion of the reaction, be refining to obtain 4- (4- { [2- (4- chlorobenzene Base) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- base Methyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (I).
How the structure of appropriate drawing is as shown in formula I for the dimension:
Step 1) the solvent be methylene chloride, dichloroethanes, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or The mixing of any one or more of tetrahydrofuran；The condensing agent is N, N'- dicyclohexylcarbodiimide (DCC), diisopropyl Carbodiimide (DIC), 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl)；The activator is 4- Dimethylamino naphthyridine (DMAP), 1- hydroxy benzo triazole (HOBt), n-hydroxysuccinimide (HOSU), Pentafluorophenol (PFP-OH)；2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- diformazan basic ring Hex- 1- alkenyl) methyl) piperazine -1- base) benzoic acid (II), 3- nitro -4- fluorobenzenesulfonamide/3- nitro -4- chlorobenzene sulfonamide, Molar ratio between condensing agent, activator is 1:1~3:1.1~3:1.2~3.
The reaction temperature of step 1) condensation reaction is 0-40 DEG C, reaction time 6-24h.
Step 1) 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) Sulfonyl)] the synthesis equation of -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III) are as follows:
Step 2) the solvent is isopropanol, dichloroethanes, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or four The mixing of any one or more of hydrogen furans or acetonitrile；The acid binding agent be sodium carbonate or potassium carbonate or cesium carbonate or triethylamine or N, N- diisopropylethylamine；4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- Base) and-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorobenzene Base) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III), oxinane -4- methylamine, tie up Molar ratio between sour agent is 1:1.1~3:1~5.
The reaction temperature of step 2) substitution reaction is 40-120 DEG C, reaction time 2-24h.
Step 2) the solvent used that refines is appointing in tetrahydrofuran, methanol, ethyl alcohol, methylene chloride or ethyl acetate One or more mixing.
Step 2) 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine - 5- base oxygroup) benzamide (I) synthesis equation are as follows:
The present invention also provides the how appropriate drawings of dimension obtained using any above-mentioned preparation method.
It has the advantages that by adopting the above technical scheme
1, the technological parameter in synthetic route of the present invention is mild, such as in room temperature, 0-40 DEG C, 40-120 DEG C, using routine Equipment can meet technological parameter requirement, consume energy low and safe and reliable, production cost can be effectively reduced, and be conducive to heavy industrialization Production.
2, synthesis step of the present invention is few, can effectively avoid the generation of by-product (impurity), improve the quality of target product, this Outside, purification number is also reduced, the yield of target product is improved, greatly reduces the production cost of target product, meanwhile, also It reduces environmental pollution.
3, the how appropriate drawing purity of dimension that the present invention is prepared reaches 99.5% or more, and single impurity meets less than 0.1% ICH quality standard.
It is further described with reference to the accompanying drawings and detailed description.
Detailed description of the invention
Fig. 1 be embodiment 1 dimension how the HPLC spectrogram of appropriate drawing；
Fig. 2 be embodiment 2 dimension how the HPLC spectrogram of appropriate drawing；
Fig. 3 be embodiment 3 dimension how the HPLC spectrogram of appropriate drawing.
Specific embodiment
In the present invention, test method without specific conditions is built usually according to normal condition or according to manufacturer The condition of view.The raw material used is that chemistry is pure.
Embodiment 1:
Step 1:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) Sulfonyl)] preparation of -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III)
Compound (II) (20.0g, 35.0mmol) is dissolved in 300mL methylene chloride (DCM), is successively added under room temperature Enter 3- nitro -4- fluorobenzenesulfonamide (8.5g, 38.5mmol), 4-dimethylaminopyridine (DMAP) (6.4g, 52.5mmol), 1- second Base-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCL) (10.1g, 52.5mmol).20~30 DEG C of temperature of control It is stirred to react 16 hours.5% acetic acid aqueous solution 100mL is added after completion of the reaction washed once, and then use 100mL water washing one again Secondary, organic phase is dry with 20g sodium sulphate, filters, is spin-dried for, and obtains fluorochemical (III) solid 26.1g, yield 96.3%, directly For feeding intake in next step.
Step 2:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine - 5- base oxygroup) benzamide (I) preparation
Fluorochemical (III) (25.0g, 32.3mmol) is dissolved in 200mL tetrahydrofuran (THF), under room temperature plus Enter oxinane -4- methylamine (5.6g, 48.5mmol) and n,N-diisopropylethylamine (DIPEA) (6.27g, 48.5mmol).It rises Temperature is stirred to react 5 hours to 60~65 DEG C, TLC detection display raw material end of reaction.It is concentrated under reduced pressure after completion of the reaction, concentrate adds Enter 500mL methylene chloride and mix 200mL purified water, water phase is isolated after stirring, organic phase is washed with 1% acetic acid aqueous solution 150mL It washs once, then primary with 200mL water washing again, organic phase is dry with 20g sodium sulphate, filters, is spin-dried for, crude product 200mL tetra- Hydrogen furans recrystallization, filtering, dry appropriate drawing highly finished product (I) the pale yellow powder 25.1g of get Wei Nai, yield 89.3%.Through applicant Mass spectral analysis is structure shown in formula I, is analyzed through HPLC, purity 99.82%, as shown in Figure 1.
Embodiment 2:
Step 1:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) Sulfonyl)] preparation of -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III)
Compound (II) (20.0g, 35.0mmol) is placed in 300mL methylene chloride (DCM), is successively added under room temperature Enter 3- nitro -4- chlorobenzene sulfonamide (9.1g, 38.5mmol), 4-dimethylaminopyridine (DMAP) (6.4g, 52.5mmol), 1- second Base-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCL) (10.1g, 52.5mmol).20~30 DEG C of temperature of control It is stirred to react 16 hours, TLC detection display raw material end of reaction.5% acetic acid aqueous solution 100mL washing one is added after completion of the reaction Secondary, then primary with 100mL water washing again, organic phase is dry with 20g sodium sulphate, filters, is spin-dried for, and it is solid to obtain chlorine-containing compound (III) Body 26.8g, yield 96.8% are directly used in and feed intake in next step.
Step 2:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine - 5- base oxygroup) benzamide (I) preparation
Chlorine-containing compound (III) (25.0g, 31.6mmol) is dissolved in 500mL acetonitrile (acetonitrile), room temperature item Be added under part oxinane -4- methylamine (5.5g, 47.5mmol) and n,N-diisopropylethylamine (DIPEA) (6.1g, 47.5mmol).It is warming up to 80~85 DEG C to be stirred to react 12 hours, TLC detection display raw material end of reaction.It depressurizes after completion of the reaction Concentration, concentrate are added 500mL methylene chloride and mix 200mL purified water, and water phase, 1% acetic acid of organic phase are isolated after stirring Aqueous solution 150mL washed once, then primary with 200mL water washing again, and organic phase is dry with 20g sodium sulphate, filters, is spin-dried for, Crude product is recrystallized with 200mL, is filtered, is dried appropriate drawing highly finished product (I) the pale yellow powder 24.1g of get Wei Nai, yield 87.6%.Through Shen Mass spectral analysis ask someone as structure shown in formula I, is analyzed through HPLC, purity 99.86%, as shown in Figure 2.
Embodiment 3:
Step 1:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) Sulfonyl)] preparation of -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III)
Compound (II) (20.0g, 35.0mmol) is dissolved in 100mLN, in dinethylformamide (DMF), room temperature condition Under sequentially add 3- nitro -4- fluorobenzenesulfonamide (8.5g, 38.5mmol), I-hydroxybenzotriazole (HOBt) (7.1g, 52.5mmol), N, N'- diisopropylcarbodiimide (DIC) (6.6g, 52.5mmol).10~20 DEG C of temperature of control is stirred to react 12 hours, TLC detection display raw material end of reaction.The mixing of 300mL methylene chloride is first added after completion of the reaction, is then added 1% Acetic acid aqueous solution 100mL washed once, and organic phase uses 100mL water washing primary again, organic phase is dry with 20g sodium sulphate, filtering, It is spin-dried for, obtains fluorochemical (III) solid 25.6g, yield 94.6% is directly used in and feeds intake in next step.
Step 2:4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine - 5- base oxygroup) benzamide (I) preparation
Fluorochemical (III) (25.0g, 32.3mmol) is dissolved in 100mLN, in dinethylformamide (DMF), is added Oxinane -4- methylamine (5.6g, 48.5mmol) and ammonium carbonate (5.1g, 48.5mmol).It is warming up to 80~85 DEG C and is stirred to react 6 Hour, TLC detection display raw material end of reaction.It is added after 500mL methylene chloride is stirred after completion of the reaction and 200mL is added Purified water, isolates water phase after stirring, organic phase washed once with 1% acetic acid aqueous solution 150mL, then be washed again with 200mL Wash primary, organic phase is dry with 20g sodium sulphate, filters, is spin-dried for, and crude product is recrystallized with 200mL tetrahydrofuran, filtering, dry Dimension how appropriate drawing highly finished product (I) pale yellow powder 23.5g, yield 83.7%.It is structure shown in formula I through applicant's mass spectral analysis, through HPLC Analysis, purity 99.81%, as shown in Figure 3.

Claims (10)

1. it is a kind of dimension how the preparation method of appropriate drawing, which is characterized in that it is described dimension how it is appropriate draw be 4- (4- [2- (4- chlorphenyl) -4, 4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) Amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (I), using following steps system :
1) by 2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane - 1- alkenyl) methyl) piperazine -1- base) benzoic acid (II), 4-dimethylaminopyridine and 3- nitro -4- fluorobenzenesulfonamide/3- nitro - 4- chlorobenzene sulfonamide is dissolved in solvent, and condensing agent is added and activator carries out condensation reaction and separates, purifies after completion of the reaction To 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- Fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorobenzene Base) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III)；
2) by 4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- obtained by step 1) Base) and-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorobenzene Base) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (III) and oxinane -4- methylamine it is molten In solvent, acid binding agent is added and carries out substitution reaction, separated after completion of the reaction, be refining to obtain 4- (4- { [2- (4- chlorobenzene Base) -4,4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- base Methyl) amino] phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (I).
2. preparation method according to claim 1, it is characterised in that: how the structure of appropriate drawing is as shown in formula I for the dimension:
3. preparation method according to claim 1, it is characterised in that: the step 1) solvent is methylene chloride, two chloroethenes The mixing of any one or more of alkane, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or tetrahydrofuran；The condensing agent For N, N'- dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- ethyl-(3- dimethylaminopropyl) Carbodiimide hydrochloride (EDC.HCl)；The activator is 4-dimethylaminopyridine (DMAP), 1- hydroxy benzo triazole (HOBt), n-hydroxysuccinimide (HOSU), Pentafluorophenol (PFP-OH)；2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygen Base) -4- (4- ((2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkenyl) methyl) piperazine -1- base) benzoic acid (II), 3- nitre Base -4- fluorobenzenesulfonamide/3- nitro -4- chlorobenzene sulfonamide, condensing agent, the molar ratio between activator are 1:1~3:1.1~3: 1.2~3.
4. preparation method according to claim 1, it is characterised in that: the reaction temperature of step 1) condensation reaction is 0-40 DEG C, reaction time 6-24h.
5. preparation method according to claim 1, it is characterised in that: step 1) 4- (4- { [2- (4- chlorphenyl) -4,4- bis- Methyl cyclohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- base] first Base } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) The synthesis equation of benzamide (III) are as follows:
6. preparation method according to claim 1, it is characterised in that: the step 2) solvent be isopropanol, dichloroethanes, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or the mixing of any one or more of tetrahydrofuran or acetonitrile；It is described to tie up Sour agent is sodium carbonate or potassium carbonate or cesium carbonate or triethylamine or N, N- diisopropylethylamine；4- (4- [2- (4- chlorphenyl) -4, 4- dimethyleyelohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- [(3- nitro -4- fluorophenyl) sulfonyl)] -2- (1H- pyrrole Cough up simultaneously [2,3-b] pyridine -5- base oxygroup) benzamide/4- (4- { [2- (4- chlorphenyl) -4,4- dimethyleyelohexane -1- alkene -1- Base] methyl } piperazine -1- base)-N- [(3- nitro -4- chlorphenyl) sulfonyl)] -2- (1H- pyrrolo- [2,3-b] pyridine -5- base Oxygroup) benzamide (III), oxinane -4- methylamine, the molar ratio between acid binding agent be 1:1.1~3:1~5.
7. preparation method according to claim 1, it is characterised in that: the reaction temperature of step 2) substitution reaction is 40-120 DEG C, reaction time 2-24h.
8. preparation method according to claim 1, it is characterised in that: the step 2) solvent used that refines is tetrahydro furan It mutters, the mixing of any one or more of methanol, ethyl alcohol, methylene chloride or ethyl acetate.
9. preparation method according to claim 1, it is characterised in that: step 2) 4- (4- { [2- (4- chlorphenyl) -4,4- bis- Methyl cyclohexane -1- alkene -1- base] methyl } piperazine -1- base)-N- ({ 3- nitro -4- [(tetrahydro -2H- pyrans -4- ylmethyl) amino] Phenyl } sulfonyl) -2- (1H- pyrrolo- [2,3-b] pyridine -5- base oxygroup) benzamide (I) synthesis equation are as follows:
10. the how appropriate drawing of dimension obtained using any preparation method of claim 1-9.
CN201811450340.9A 2018-11-30 2018-11-30 It is a kind of dimension how the preparation method and products thereof of appropriate drawing Pending CN109438441A (en)

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Application publication date: 20190308