CN101935317A - Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof - Google Patents
Synthesizing method of 2-methyl-7-(substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and intermediate thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title abstract description 25
- 230000002194 synthesizing effect Effects 0.000 title abstract 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 24
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims abstract description 11
- 238000006467 substitution reaction Methods 0.000 claims abstract description 11
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 6
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 93
- 238000006243 chemical reaction Methods 0.000 claims description 89
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- VAATWVRXPRDPPM-UHFFFAOYSA-N 2-chloro-4-methylsulfanylpyrimidine Chemical class CSC1=CC=NC(Cl)=N1 VAATWVRXPRDPPM-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 20
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 238000010189 synthetic method Methods 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- LCNPRNSOGSLJFZ-UHFFFAOYSA-N 4,5-dichloropyrimidin-2-amine Chemical compound NC1=NC=C(Cl)C(Cl)=N1 LCNPRNSOGSLJFZ-UHFFFAOYSA-N 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- KVNQTSPPLQWYSO-UHFFFAOYSA-N 2,5-dichloro-4-methylsulfanylpyrimidine Chemical compound CSC1=NC(Cl)=NC=C1Cl KVNQTSPPLQWYSO-UHFFFAOYSA-N 0.000 abstract 1
- GOCAKGMHAFDMNQ-UHFFFAOYSA-N 2-amino-5-chloro-1h-pyrimidin-6-one Chemical compound NC1=NC(=O)C(Cl)=CN1 GOCAKGMHAFDMNQ-UHFFFAOYSA-N 0.000 abstract 1
- FDDDQJSVMQBCFM-UHFFFAOYSA-N 5-chloro-4-methylsulfanylpyrimidin-2-amine Chemical compound CSC1=NC(N)=NC=C1Cl FDDDQJSVMQBCFM-UHFFFAOYSA-N 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- -1 hydroxyl compound Chemical class 0.000 abstract 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 abstract 1
- 239000000047 product Substances 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 239000012141 concentrate Substances 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 230000035484 reaction time Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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Abstract
The invention relates to an synthesizing method of 2-methyl-7-( substituted pyrimidine-4-amino)-4-(substituted piperazine-1-base) piperidine-1-base) isoindoline-1-ketone and an intermediate thereof, mainly solving the technical problems of overlength single-line synthetic route, difficult separation and purification, low productivity, high synthesizing cost, narrow applicability, and the like of the traditional synthesizing method. The process method comprises the following steps of: carrying out substitution reaction on 2,4,5-trichloropyrimidine as a raw material and sodium methyl mercaptide to generate the intermediate, i.e. 2,5-dichloro-4-methylthiopyrimidine; then carrying out the substitution reaction with aromatic amine to generate the intermediate, i.e. 2-aromatic amino-4-methylthio-5-chloropyrimidine; then hydrolyzing the methylthio to generate the intermediate, i.e. 2-aromatic amino-4-hydroxy-5-chloropyrimidine; enabling a hydroxyl compound to generate dichloride under the action of phosphorus oxychloride; and finally carrying out the substitution reaction with amine to obtain the 2-methyl-7-(5-chlorine-2-aromatic amido-pyrimidine-4-amino)-4-(4-(4-methyl piperazine-1-base) piperidine-1-base) isoindoline-1-ketone under the action of hydrogen chloride ethyl acetate.
Description
Technical field:
The present invention relates to the synthetic method of a class important drugs molecule 2-methyl-7-(substituted pyrimidines-4-amino)-4-(substituted piperidine-1-yl) 1-isoindolinone and intermediate, be 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone and intermediate 2-aromatic amino-4, the synthetic method of 5-dichloro pyrimidine.
Background technology:
2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone is the important drug molecule of a class, it is as focal adhesion kinase (focal adhesion kinase, FAK) inhibitor, therefore the symptom that can be used as the pharmacological agent signal cascade obstacle (malfunction of signal cascades) relevant with focal adhesion kinase and produce has anti-tumor bioactivity.The synthetic route of having only one piece of PCT patent application (WO 2006/021457) report related compound at present.But we find in experimentation, compound 7 and the 1 reaction conditions (K at report
2CO
3/ DMSO/60 ℃) reaction down, product is very complicated, can not obtain target compound.Even by the change reaction times, temperature of reaction, feed ratio, optimal conditions such as order of addition(of ingredients), still very difficulty is taken target compound.
The synthetic route of such compound of WO 2006/021457 report is as follows:
We have found a method for preparing compound 9 also by groping reaction conditions simultaneously, and are as follows:
But this method isolated yield is not high, has only about 20%.And, make the scale that feeds intake each time be restricted because this method need be used microwave heating, therefore be not suitable for mass preparation.
Summary of the invention:
The object of the present invention is to provide the new synthetic method of a kind of important drugs molecule 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone, mainly solve the separation and purification difficulty that existing synthetic method single line synthetic route is long and exist, productive rate is low, synthetic cost height, technical problem such as suitability is wideless.We search out a class important drugs molecule 2-aromatic amino-4 in experiment, the preparation method of 5-dichloro pyrimidine and use it for Synthetic 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone.
Technical scheme of the present invention: the synthetic method of 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone, may further comprise the steps: with 2,4,5-trichloropyrimidine 1 is a raw material, by generating intermediate 2 with sodium methyl mercaptide generation substitution reaction, 5-two chloro-4-methylthiopyrimidines 2 take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the substitution reaction with aromatic amine 3 then; Intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 will be generated then after 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 hydrolysis; 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 generates 2-aromatic amino-4,5-dichloro pyrimidine 6 under the phosphorus oxychloride effect; With amine 7 substitution reactions taking place obtains 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 at last under the ethyl acetate solution effect of hydrogenchloride.Chemical equation is as follows:
The first step reaction is that 5-trichloropyrimidine 1 is dissolved in organic solvent (as tetrahydrofuran (THF), acetonitrile, Virahol), then the sodium methyl mercaptide aqueous solution slowly is added drop-wise in the reaction solution with 2,4.Dropwise, reaction solution at room temperature stirred 12～24 hours.Obtain pure product 2 after the aftertreatment, 5-two chloro-4-methylthiopyrimidines 2.
The reaction of second step is that 5-two chloro-4-methylthiopyrimidines 2 and aromatic amine 3 are dissolved in propyl carbinol or Virahol with 2, and the ethyl acetate solution with hydrogenchloride slowly is added drop-wise in the reaction solution then.Dropwise, reaction solution is heated to reflux temperature, and stirs 16～24 hours under this temperature.Obtain pure product 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the aftertreatment.
Three-step reaction is heated to backflow with reaction solution then for 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 is joined aqueous hydrochloric acid, and reaction solution stirred under this temperature 12～16 hours.Obtain pure product 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 after the aftertreatment.
Four-step reaction is heated to backflow with reaction mixture then for 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 is joined in the phosphorus oxychloride in batches, and reaction solution stirred under this temperature 1～4 hour.Obtain pure product 2-aromatic amino-4 after the aftertreatment, 5-dichloro pyrimidine 6.
The reaction of the 5th step is that 5-dichloro pyrimidine 6 and amine 7 join in propyl carbinol or the aqueous isopropanol, heating for dissolving with 2-aromatic amino-4.Drip the ethyl acetate solution of hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2-4 hour under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-aromatic amino-4, the ethyl acetate solution of 5-dichloro pyrimidine 6 and hydrogenchloride, this stirs reaction solution 2-4 hour under reflux temperature again.Obtain product 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 behind the recrystallization.
The invention has the beneficial effects as follows: the invention provides a kind of 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 synthetic routes of novelty, can prepare this class important drugs molecule quickly and easily from raw material cheap, that be easy to get.Compare with the WO 2006/021457 of this compounds of reported first, the preparation that the present invention is not only successful target compound, and aftertreatment is also more easy.Compare with the microwave heating process that we optimized, productive rate has also improved 27%.
Embodiment: following example helps to understand content of the present invention, the present invention includes but is not limited to following related content:
Embodiment
1.2, the synthesis technique one of 5-two chloro-4-methylthiopyrimidines 2
With 2,4, (80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL) to 5-trichloropyrimidine 1, and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 80g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 93%)
Proton nmr spectra
1H-NMR (DMSO, 400MHz): δ 8.19 (s, 1H), 2.58 (s, 3H); MS (ESI) m/e (M+H
+) 195.
2.2, the synthesis technique two of 5-two chloro-4-methylthiopyrimidines 2
With 2,4, (80g 0.44mol) is dissolved in acetonitrile (1000mL) to 5-trichloropyrimidine 1, and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 75g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 87%)
3.2, the synthesis technique three of 5-two chloro-4-methylthiopyrimidines 2
With 2,4, (80g 0.44mol) is dissolved in Virahol (1000mL) to 5-trichloropyrimidine 1, and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then.Dropwise, reaction solution at room temperature stirred 24 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 70g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 82%)
4.2, the synthesis technique four of 5-two chloro-4-methylthiopyrimidines 2
With 2,4, (80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL) to 5-trichloropyrimidine 1, and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then.Dropwise, reaction solution at room temperature stirred 12 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 75g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 87%)
5.2, the synthesis technique five of 5-two chloro-4-methylthiopyrimidines 2
With 2,4, (80g 0.44mol) is dissolved in tetrahydrofuran (THF) (1000mL) to 5-trichloropyrimidine 1, and (150g 0.45mol) slowly is added drop-wise in the reaction solution with the sodium methyl mercaptide aqueous solution of concentration expressed in percentage by weight 21% then.Dropwise, reaction solution at room temperature stirred 18 hours.Reaction solution is poured in the water of 200mL.The ethyl acetate extraction of mixed solution usefulness 1L three times.The organic phase anhydrous sodium sulfate drying that merges.Siccative is filtered, and filtrate concentrates the dried pure product 2 of 78g that obtain, 5-two chloro-4-methylthiopyrimidines 2 (productive rates: 91%)
The synthesis technique one of (6.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in propyl carbinol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 24 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 170g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: proton nmr spectra 88%) that obtains
1H-NMR (DMSO, 400MHz): δ 8.44 (m, 1H), 8.06 (m, 1H), 7.71 (s, 1H), 7.01-6.93 (m, 2H), 6.91-6.90 (m, 1H), 3.93 (s, 3H), 2.61 (s, 3H); MS (ESI) m/e (M+H
+) 282.
The synthesis technique two of (7.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in Virahol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 24 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 100g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: 52%) that obtains
The synthesis technique three of (8.2-2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11
With 2,5-two chloro-4-methylthiopyrimidines 2 (133g, 0.682mol) and ORTHO ANISIDINE (84.5g, 0.687mol) 10 are dissolved in propyl carbinol (2000mL), (4M, 170mL 0.68mol) slowly are added drop-wise in the reaction solution with the ethyl acetate solution of hydrogenchloride then.Dropwise, reaction solution is heated to reflux temperature, and stirs 16 hours under this temperature.Reaction solution is cooled to room temperature, and the solid filtering in the reaction solution falls, and filtrate concentrating done, and the thick product that obtains is put in the saturated sodium bicarbonate aqueous solution of 500mL, the ethyl acetate extraction of mixed solution usefulness 400mL three times.The organic phase anhydrous sodium sulfate drying.Siccative is filtered, and filtrate concentrates the dried pure product 2-of 150g (2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11 (productive rate: 78%) that obtains
The synthesis technique one of (9.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 6M, then reaction solution is heated to backflow, and reaction solution stirred 16 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 73g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 48%) with the ethyl acetate washing after drying of 600mL again
Proton nmr spectra
1H-NMR (DMSO, 400MHz): δ 11.80 (s, 1H), 8.48 (s, 1H), 8.23 (m, 1H), 7.95 (s, 1H), 7.06-7.01 (m, 2H), 6.94-6.90 (m, 1H), 3.87 (s, 3H); MS (ESI) m/e (M+H
+) 252.
The synthesis technique two of (10.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 3M, then reaction solution is heated to backflow, and reaction solution stirred 16 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 50g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 33%) with the ethyl acetate washing after drying of 600mL again
The synthesis technique three of (11.2-2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12
(170.0g 0.605mol) joins the aqueous hydrochloric acid (5.0L) of 6M, then reaction solution is heated to backflow, and reaction solution stirred 12 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-methylthio group-5-chloropyrimide 11.After the reaction solution cooling, concentrate and obtain thick product.Thick product is dissolved in pyridine (200mL), then mixing solutions is poured in the water of 800mL, the solid of generation obtains the pure product 2-of 70g (2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12 (productive rate: 46%) with the ethyl acetate washing after drying of 600mL again
(12.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique one of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 1 hour under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 20g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 81%)
Proton nmr spectra
1H-NMR (CDCl3,400MHz): δ 8.31-8.28 (m, 2H), 7.81 (s, 1H), 6.98-6.91 (m, 2H), 6.84-6.82 (m, 1H), 3.82 (s, 3H); MS (ESI) m/e (M+H
+) 270.
(13.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique two of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 2 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 18g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 73%)
(14.2-2 '-p-methoxy-phenyl amino)-4, the synthesis technique three of 5-dichloro pyrimidine 13
(23.0g 91.4mmol) joins in the phosphorus oxychloride of 300mL in batches, then reaction mixture is heated to backflow, and reaction solution stirred 4 hours under this temperature with 2-(2 '-p-methoxy-phenyl amino)-4-hydroxyl-5-chloropyrimide 12.Excessive phosphorus oxychloride under reduced pressure distilled remove, the crude product that obtains is dissolved in ethyl acetate.Organic phase is used anhydrous sodium sulfate drying after washing with saturated sodium bicarbonate aqueous solution.Remove by filter siccative, filtrate concentrating obtains the pure product 2-of 17g (2 '-p-methoxy-phenyl amino)-4,5-dichloro pyrimidine 13 (productive rate: 69%)
15.2-the synthesis technique one of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the butanol solution of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the ethyl acetate solution (10mL) of 4M hydrogenchloride, this stirs reaction solution 2 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 4g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 47%) with recrystallizing methanol then
Proton nmr spectra
1H-NMR (CDCl
3, 400MHz): δ 10.46 (s, 1H), 8.59-8.56 (m, 1H), 8.28-8.26 (m, 1H), 8.04 (s, 1H), 7.38 (s, 1H), 7.02 (d, J=8.8Hz, 1H), 6.94-6.90 (m, 2H), 6.85-6.83 (m, 1H), 4.48 (s, 2H), 3.84 (s, 3H), 3.27-3.24 (m, 2H), 3.14 (s, 3H), 2.72-2.69 (m, 11H), 2.24 (s, 3H), and 1.97-1.90 (m, 2H), 1.66-1.56 (m, 2H); MS (ESI) m/e (M+H
+) 577.
16.2-the synthesis technique two of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the aqueous isopropanol of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 2 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the ethyl acetate solution (10mL) of 4M hydrogenchloride, this stirs reaction solution 2 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 2g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 24%) with recrystallizing methanol then
17.2-the synthesis technique three of methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14
With 2-(2 '-p-methoxy-phenyl amino)-4, (10g, 37mmol) (5g 14.6mmol) joins in the butanol solution of 2.5L heating for dissolving to 5-dichloro pyrimidine 13 with amine 7.Drip the ethyl acetate solution (20mL) of 4M hydrogenchloride then.Reaction solution is heated to backflow, and stirs 4 hours under this temperature.Reaction solution is cooled to 100 ℃ then, adds 2-(2 '-p-methoxy-phenyl amino)-4, (5g, 18.5mmol) and the hydrogenchloride ethyl acetate solution (10mL) of 4M, this stirs reaction solution 4 hours under reflux temperature 5-dichloro pyrimidine 13 again.When the detection reaction end, reaction solution concentrates to be done.Crude product washs with ethyl acetate, obtains 3.5g product 2-methyl-7-(5-chloro-2-(2-anisidine) pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 14 (productive rate: 42%) with recrystallizing methanol then.
Claims (7)
1. the synthetic method of a 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone may further comprise the steps:
The first step: with 2,4,5-trichloropyrimidine 1 is a raw material, by generating intermediate 2,5-two chloro-4-methylthiopyrimidines 2 with sodium methyl mercaptide generation substitution reaction;
Second step: 2,5-two chloro-4-methylthiopyrimidines 2 take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the substitution reaction with aromatic amine 3;
The 3rd step: will generate intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 after 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 hydrolysis then;
The 4th step: 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 generates 2-aromatic amino-4,5-dichloro pyrimidine 6 under the phosphorus oxychloride effect;
The 5th step: substitution reaction takes place with amine 7 and obtains 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 in last 2-aromatic amino-4,5-dichloro pyrimidine 6 under the ethyl acetate solution effect of hydrogenchloride;
Chemical equation is as follows:
2. 2-aromatic amino-4, the synthetic method of 5-dichloro pyrimidine may further comprise the steps:
The first step: with 2,4,5-trichloropyrimidine 1 is a raw material, by generating intermediate 2,5-two chloro-4-methylthiopyrimidines 2 with sodium methyl mercaptide generation substitution reaction;
Second step: 2,5-two chloro-4-methylthiopyrimidines 2 take place to generate intermediate 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the substitution reaction with aromatic amine 3;
The 3rd step: will generate intermediate 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 after 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 hydrolysis then;
The 4th step: 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 generates 2-aromatic amino-4,5-dichloro pyrimidine 6 under the phosphorus oxychloride effect; Reaction formula is as follows
3. synthetic method according to claim 1 and 2, it is characterized in that, the first step reaction is with 2,4,5-trichloropyrimidine 1 is dissolved in organic solvent and is selected from a kind of in tetrahydrofuran (THF), acetonitrile or the Virahol, slowly is added drop-wise to the sodium methyl mercaptide aqueous solution in the reaction solution then, dropwise, reaction solution at room temperature stirred 12～24 hours, obtained pure product 2 after the aftertreatment, 5-two chloro-4-methylthiopyrimidines 2.
4. synthetic method according to claim 1 and 2, it is characterized in that, the reaction of second step is with 2,5-two chloro-4-methylthiopyrimidines 2 and aromatic amine 3 are dissolved in propyl carbinol or Virahol, ethyl acetate solution with hydrogenchloride slowly is added drop-wise in the reaction solution then, dropwises, and reaction solution is heated to reflux temperature, and under this temperature, stirred 16～24 hours, obtain pure product 2-aromatic amino-4-methylthio group-5-chloropyrimide 4 after the aftertreatment.
5. synthetic method according to claim 1 and 2, it is characterized in that, three-step reaction is for to join aqueous hydrochloric acid with 2-aromatic amino-4-methylthio group-5-chloropyrimide 4, then reaction solution is heated to backflow, reaction solution stirred under this temperature 12～16 hours, obtained pure product 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 after the aftertreatment.
6. synthetic method according to claim 1, it is characterized in that, four-step reaction is with the 2-aromatic amino-4-hydroxyl-5-chloropyrimide 5 joins in the phosphorus oxychloride in batches, then reaction mixture is heated to backflow, reaction solution stirred under this temperature 1～4 hour, obtain pure product 2-aromatic amino-4 after the aftertreatment, 5-dichloro pyrimidine 6.
7. according to the synthetic method of the described 2-methyl-7-of claim 1 (5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone, it is characterized in that, the reaction of the 5th step is with 2-aromatic amino-4,5-dichloro pyrimidine 6 and amine 7 join in propyl carbinol or the aqueous isopropanol, heating for dissolving, drip the ethyl acetate solution of hydrogenchloride then, reaction solution is heated to backflow, and under this temperature, stirred 2-4 hour, reaction solution is cooled to 100 ℃ then, add 2-aromatic amino-4, the ethyl acetate solution of 5-dichloro pyrimidine 6 and hydrogenchloride, this stirs reaction solution 2-4 hour under reflux temperature again, obtains product 2-methyl-7-(5-chloro-2-aromatic amino pyrimidine-4-amino)-4-(4-(4-methylpiperazine-1-yl) piperidines-1-yl) 1-isoindolinone 8 behind the recrystallization.
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| CN110294715A (en) * | 2019-06-24 | 2019-10-01 | 南京普锐达医药科技有限公司 | Synthesis method of 2,4, 6-trichloro-5-methoxypyrimidine |
| CN110372605A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
| CN116768809A (en) * | 2023-06-28 | 2023-09-19 | 上海泰坦科技股份有限公司 | A kind of preparation method of 2,4-dichloro-6-(methylthio)-1,3,5-triazine |
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| CN110294715A (en) * | 2019-06-24 | 2019-10-01 | 南京普锐达医药科技有限公司 | Synthesis method of 2,4, 6-trichloro-5-methoxypyrimidine |
| CN110372605A (en) * | 2019-06-24 | 2019-10-25 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
| CN110294715B (en) * | 2019-06-24 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2,4, 6-trichloro-5-methoxypyrimidine |
| CN110372605B (en) * | 2019-06-24 | 2022-05-13 | 南京普锐达医药科技有限公司 | Synthesis method of 2-methylthio-4, 6-dichloro-5-nitropyrimidine |
| CN116768809A (en) * | 2023-06-28 | 2023-09-19 | 上海泰坦科技股份有限公司 | A kind of preparation method of 2,4-dichloro-6-(methylthio)-1,3,5-triazine |
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