CN101967140A - Deuterated crizotinib as well as derivant, preparation method and application thereof - Google Patents
Deuterated crizotinib as well as derivant, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medical compound synthesis, and in particular relates to deuterated crizotinib as well as a preparation method and application thereof. The structural formulas of the deuterated crizotinib and a derivant thereof are showed as (I) or (II). The crizotinib deuterated derivant provided by the invention has the same medical effect as crizotinib, thereby providing a new compound for synthesizing a new antineoplastic agent and a new way for the synthesis of the antineoplastic agent.
Description
(1) technical field
The invention belongs to pharmaceutical compound synthetic field, particularly deuterium Dai Keli azoles base of a fruit Buddhist nun and its production and application.
(2) background technology
Nonsmall-cell lung cancer is modal lung cancer type, accounts for 80% to 85% of all patients with lung cancer, and wherein the part patient is attended by transgenation.Genic mutation type nonsmall-cell lung cancer patient group is mainly non-smoker and ex-smoker.WHO's statistics, present stage, annual newly-increased patients with lung cancer 1,200 ten thousand people that make a definite diagnosis in the whole world, annual because of lung cancer death 8,000,000 people.
The malignant tumour size that can effectively dwindle late gene mutant nonsmall-cell lung cancer (NSCLC) patient through clinical verification by azoles base of a fruit Buddhist nun (Crizotinib) in the gram of Pfizer pharmaceutical Co. Ltd research and development.One clinical trial phase confirms, azoles base of a fruit Buddhist nun tells on to 90% late gene mutant nonsmall-cell lung cancer patient in the gram, and wherein 57% 8 week of patient's oral pharmaceutical back tumours are obviously shunk.
In recent years, along with the further of antitumor drug research goed deep into, provide new having to dwindle the key that big or small compound that acts on of malignant tumour and preparation method thereof becomes the development of new antitumor drug.
(3) summary of the invention
The object of the present invention is to provide a kind of deuterium Dai Keli azoles base of a fruit Buddhist nun and its production and application, in deuterium generation, have been carried out at two positions in azoles base of a fruit Buddhist nun (Crizotinib) structure in the gram, for the synthesizing new antitumor drug provides new compound, also open up new approach for antitumor drug synthetic.
The technical solution used in the present invention is as follows:
Deuterium Dai Keli azoles base of a fruit Buddhist nun and derivative thereof, its structural formula are as (I) or (II):
Wherein, R is hydrogen or tert-butoxycarbonyl.
The present invention also provides the intermediate of preparation deuterium Dai Keli azoles base of a fruit Buddhist nun and derivative process thereof, shown in 5a or 5b:
The preparation method of described deuterium Dai Keli azoles base of a fruit Buddhist nun and derivative thereof; be dissolved in N earlier with the formula 5b compound in formula 5a compound and non-deuterium generation or with the formula 5a compound and the formula 5b compound in non-deuterium generation; dinethylformamide (DMF); diethylamide (DMA); dioxane or triethylamine; add yellow soda ash afterwards; salt of wormwood; Potassium ethanoate or triethylamine under the nitrogen protection, add palladium successively; triphenyl phosphorus; be warming up to 80 to 150 ℃ of heated and stirred 3 to 20h; be cooled to room temperature, add the ethyl acetate dilution, filter; dry; concentrate, silica gel column chromatography separates, and obtains deuterium Dai Keli azoles base of a fruit Buddhist nun derivative.
Described deuterium Dai Keli azoles base of a fruit Buddhist nun derivative is dissolved in the organic solvent,, monitors when derivative disappears to wherein feeding hydrogen chloride gas, concentrate, transferring PH is alkalescence, and conventional afterwards aftertreatment obtains deuterium Dai Keli azoles base of a fruit Buddhist nun, and described organic solvent is dioxane or tetrahydrofuran (THF).
The preparation method of formula 5a compound is as follows:
The reductive agent in formula 1a compound and deuterium generation is dissolved in room temperature reaction in the organic solvent, obtains formula 2a compound, compound 2a is split through enzyme obtain optical isomer 2aR and 2aS; Wherein the reductive agent in deuterium generation is meant the deuterium lithium aluminium hydride (LiAlD in generation
4), the sodium borohydride (NaBD in deuterium generation
4), the acetic acid sodium borohydride (NaB (0Ac) in deuterium generation
3D) and the sodium cyanoborohydride (NaBCND in deuterium generation
3) in a kind of, organic solvent is meant a kind of in benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, dioxane, the trichloromethane;
Under the nitrogen atmosphere, triphenyl phosphorus and DEAD are dissolved in tetrahydrofuran (THF), dioxane, N, in dinethylformamide, diethylamide, dioxane or the triethylamine, be cooled to 0 ℃, under the magnetic agitation, the tetrahydrofuran solution of 3-hydroxyl-2-nitropyridine and compound 2aR adds by constant pressure funnel; Resulting orange clear solution rises to stirring at room, and thin-layer chromatography shows that compound 2aR disappears, and conventional aftertreatment concentrates and obtains solid chemical compound 3a; The amount of substance ratio that wherein feeds intake is: 2aR: triphenyl phosphorus: DEAD: 3-hydroxyl-2-nitropyridine is 1: 1-3: 1-3: 1-3;
In reaction vessel, add acetic acid successively, ethanol, formula 3a compound, reduced iron powder slowly is heated to and refluxes and keep backflow 0-5h, is cooled to concentrate after the room temperature to remove most of solvent, add isopyknic ethyl acetate and water then, slowly inject the saturated sodium carbonate solution neutralization again in above-mentioned mixed system, conventional aftertreatment concentrates and obtains formula 4a compound, wherein the mole dosage of raw material reduced iron powder be formula 3a compound 8-20 doubly; Compound 4a is dissolved in the acetonitrile, cooling, N-bromosuccinimide slowly adds in batches, cooling continues to stir conventional afterwards aftertreatment, column chromatography down, obtain formula 5a compound, wherein the N-bromosuccinimide mole dosage be formula 4a compound 0.6-3.0 doubly;
The preparation method of described intermediate formula 5b compound is as follows:
The reductive agent in 1b and deuterium generation is dissolved in room temperature reaction in the organic solvent, obtains compound 2b; Wherein the reductive agent in deuterium generation is meant the deuterium lithium aluminium hydride (LiAlD in generation
4), the sodium borohydride (NaBD in deuterium generation
4), the acetic acid sodium borohydride (NaB (OAc) in deuterium generation
3D) and the sodium cyanoborohydride (NaBCND in deuterium generation
3) in a kind of, organic solvent is meant a kind of in benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or the ethanol;
Compound 2b is dissolved in methylene dichloride, benzene, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or the ethanol, adds organic amine, be cooled to-10 to 10 ℃, slowly drip methylsulfonyl chloride, add N, N-dimethyl aminopyridine (DMAP); Be warmed up to room temperature behind reinforced the finishing, continue to stir 1-8h, in reaction system, add entry and get compound 3b through conventional aftertreatment; The amount of substance ratio that feeds intake is: 2b: organic amine: methylsulfonyl chloride: DMAP is 1: 1-5: 1-5: 0.01-0.25;
4-iodo pyrazoles is dissolved in exsiccant N, dinethylformamide, diethylamide, dioxane, in tetrahydrofuran (THF) or the toluene, nitrogen atmosphere, under 0 ℃, slowly adding total mole dosage in batches is 4-iodo pyrazoles 1.0-3.0 sodium hydrogen doubly; Reaction mixture-10 ℃ adds compound 3b after continuing down to stir to 10 ℃, and temperature of reaction rises to 60-120 ℃ and continue to stir, and after the question response system temperature is reduced to room temperature, adds the shrend reaction of going out, the concentrated compound 4b that obtains of conventional aftertreatment;
Under the nitrogen atmosphere, Potassium ethanoate is added exsiccant N, in dinethylformamide, diethylamide, dioxane, tetrahydrofuran (THF) or the toluene, to wherein adding formula 4b compound, connection borine Knit-the-brows is which alcohol ester successively, palladium, triphenyl phosphorus is warming up to 80-150 ℃ and stirs 1-24h, and reaction system is cooled to room temperature, diatomite filtration, conventional aftertreatment gets the 5b compound; The amount of substance ratio that feeds intake is: formula 4b compound: Potassium ethanoate: connection borine Knit-the-brows is which alcohol ester: palladium, triphenyl phosphorus are 1: 1-5: 0.8-2.0: 0.01-0.15: 0.01-0.4;
Described deuterium Dai Keli azoles base of a fruit Buddhist nun is having good application aspect the preparation treatment cancer drug.
Lung cancer particularly.
The synthetic deuterium Dai Keli azoles base of a fruit Buddhist nun of institute of the present invention (Crizotinib) derivative have to the gram in the similar biological activity of azoles base of a fruit Buddhist nun (Crizotinib), the target spot of effect all is a modification lymphoma kinases ALK (Anaplastic Lymphoma Kinase).
The present invention has following advantage with respect to prior art:
In the gram provided by the present invention azoles base of a fruit Buddhist nun (Crizotinib) deuterium for derivative have with the gram in the same drug effect of azoles base of a fruit Buddhist nun (Crizotinib), thereby, also open up a new way for the synthetic of antitumor drug for the synthesizing new antitumor drug provides new compound.
(4) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
Compound 1b (10g, 50.25mmol) be dissolved in anhydrous methanol (100mL), place the single necked round bottom flask of 250mL, room temperature, under the magnetic agitation, add in batches sodium borohydride (3.8g, 100mmol), add the back that finishes and continue to stir 1h, add the 2mL shrend and go out, add 100mL water again, ethyl acetate extraction (150mL * 2) after concentrating, organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying filters, filtrate concentrate clear, colorless thickness oily product (leave standstill after a day and become white solid) compound 2b (9.6g, productive rate 95%).
1H?NMR(400MHz，CDCl
3)δ1.42(s，9H)，1.51(m，2H)，1.84(m，2H)，3.03(m，2H)，3.85(m，3H).
Compound 2b (9.6g 47.8mmol) is dissolved in methylene dichloride (120mL), places three mouthfuls of round-bottomed flasks of 250mL, add triethylamine (5g 48mmol), is cooled to 0 ℃, slowly drip methylsulfonyl chloride (5.5g, 47.8mmol), add DMAP (0.6g, 4.7mmol).Be warmed up to room temperature behind reinforced the finishing, continue to stir 3h, in reaction system, add entry (50mL), dichloromethane extraction, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, filtering and concentrating gets white solid compound 3b (13g, productive rate 98%).
1H?NMR(400MHz，CDCl
3)δ1.45(s，9H)，1.83(m，2H)，1.95(m，2H)，3.02(s，3H)，3.28(m，2H)，3.70(m，2H)，4.88(m，1H).
(8.2g 42.4mmol) is dissolved in exsiccant DMF (150mL) to 4-iodo pyrazoles, places three mouthfuls of round-bottomed flasks of 250mL, and nitrogen atmosphere under 0 ℃, slowly adds sodium hydrogen (2g, 50.6mmol, content 60%) in batches.After reaction mixture continues down for 0 ℃ to stir 1h, add compound 3b, temperature of reaction rises to 120 ℃ and continuation stirring 12h, after the question response system temperature is reduced to room temperature, add water (2mL) cancellation reaction, concentrate and remove most of DMF, add entry (100mL) then, ethyl acetate extraction (150mL * 2) merges organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrate, use silica gel column chromatography, ethyl acetate: sherwood oil=1: 10 is an eluent, the component that will contain compound 4b merges, and concentrates and obtains white solid compound 4b (25g, productive rate 79%).
1H?NMR(400MHz，CDCl
3)δ1.47(s，9H)，1.86(m，2H)，2.09(m，2H)，2.87(m，2H)，4.26(m，3H)，7.45(s，1H)，7.51(s，1H).
(5.2g 53.2mmol) places three mouthfuls of round-bottomed flasks of 250mL dewater (30mm, 180 ℃ to Potassium ethanoate, 10min), under the nitrogen atmosphere, add exsiccant DMF, (5g 13.3mmol), joins which alcohol ester (3.7g of borine Knit-the-brows to wherein adding compound 4b successively, 14.6mmol), palladium (150mg, 0.67mmol), triphenyl phosphorus (370mg, 1.4mmol), vacuumize displacement nitrogen after, be warming up to 80 ℃ and stir 2h.Reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing, concentrate remove most of DMF after, add entry (100mL) then, ethyl acetate extraction (150mL * 2), merge organic phase, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrate, use silica gel column chromatography, ethyl acetate: sherwood oil=1: 5 is an eluent, the component that will contain compound 5b merges, and concentrates and obtains white solid compound 5b (2.2g, productive rate 45%).
1H?NMR(400MHz，CDCl
3)δ1.27(s，12H)，1.47(s，9H)，1.88(m，2H)，2.12(m，2H)，2.90(m，2H)，4.26(m，3H)，7.73(s，1H)，7.79(s，1H).
Synthetic route 2
Compound 1a (10g, 48.5mmol) be dissolved in anhydrous methanol (100mL), place the single necked round bottom flask of 250mL, room temperature under the magnetic agitation, adds deuterium in batches for sodium borohydride (3g, 78mmol), add the back that finishes and continue to stir 1h, add the 2mL shrend and go out, add 100mL water again after concentrating, ethyl acetate extraction (150mL * 2), organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying, filter, filtrate concentrate clear, colorless thickness oily product (leave standstill after a day and become white solid), compound 2a (10g, productive rate 99%).
1H?NMR(400MHz，CDCl
3)δ1.65(s，3H)，7.03(t，J＝8.4Hz，1H)，7.27(dd，J＝4.8Hz，8.8Hz，1H).
Compound 2a splits through enzyme and obtains two optical isomer 2aR and 2aS.2aR is used for the synthetic of compound 3a.
Under the nitrogen atmosphere, triphenyl phosphorus (17.6g, 67.2mmo l) and DEAD (11.7g, 67.2mmol) be dissolved in tetrahydrofuran (THF) (200mL), place three mouthfuls of round-bottomed flasks of 1L, be cooled to 0 ℃, under the magnetic agitation, (7.4g, 53mmol) (10g, tetrahydrofuran solution 48mmol) (200mL) presses dropping funnel to join in the round-bottomed flask by weighing apparatus to 3-hydroxyl-2-nitropyridine with compound 2aR.Resulting orange clear solution rises to stirring at room 3h, thin-layer chromatography shows that compound 2aR disappears, reaction solution is transferred in the 500mL single necked round bottom flask, concentrate, column chromatography, ethyl acetate: sherwood oil=1: 5 is an eluent, the component that will contain compound 3a merges, concentrate and obtain pink solid compound 3a (16g, productive rate 99%).
1H?NMR(400MHz，CDCl
3)δ1.84(s，3H)，7.03(d，J＝8.4Hz，8.8Hz，1H)，7.21(d，J＝1.6Hz，4.4Hz，1H)，7.32(dd，J＝4.8Hz，8.4Hz，1H)，7.38(dd，J＝4.8Hz，8.4Hz，1H)，8.04(dd，J＝1.2Hz，4.4Hz，1H).
In the round-bottomed flask of 2L, add acetic acid (900mL) successively, ethanol (700mL), compound 3a (16g, 48.5mmol), reduced iron powder (27g, 485mmol), slowly be heated to and reflux and maintenance backflow 1h, be cooled to concentrate after the room temperature and remove most of acetate and ethanol, add ethyl acetate (500mL) and water (500mL) then, in above-mentioned mixed system, slowly neutralize again as saturated sodium carbonate solution.Ethyl acetate extraction ((500mL * 2) merge organic phase, use saturated sodium bicarbonate (200mL) successively, water (200mL), and saturated aqueous common salt (200mL), washing, anhydrous magnesium sulfate drying filters, and concentrates and obtains compound 4a, pink solid, 13g, productive rate 90%.
1H?NMR(400MHz，CDCl
3)δ1.80(s，3H)，4.83(br，2H)，6.45(dd，J＝4.2Hz，8.0Hz，1H)，6.68(dd，J＝1.2Hz，7.6Hz，1H)，7.04(dd，J＝8.0Hz，8.8Hz，1H)，7.26(dd，J＝4.4Hz，5.2Hz，1H)，7.59(dd，J＝1.6Hz，5.6Hz，1H).
(13g 43.3mmol) is dissolved in the round-bottomed flask that acetonitrile (150mL) places 250mL to compound 4a, is cooled to 0 ℃, and (7.8g 43.3mmol) slowly adds NBS in batches, and adding finishes back 0 ℃ continues to stir 30min down.Reaction solution is concentrated, column chromatography, ethyl acetate: sherwood oil=1: 1 be an eluent, and the component that will contain compound 5a merges, the concentrated brown solid compound 5a (9g, productive rate 55%) that obtains.
1HNMR(400MHz，CDC?l
3)δ1.81(s，3H)，4.82(br，2H)，6.84(d，J＝1.6Hz，1H)，7.08(dd，J＝8Hz，8.8Hz，1H)，7.32(dd，J＝4.8Hz，8.8Hz，1H)，7.26(d，J＝2.0Hz，1H).
Compound 5a (2.6g, 7mmol) (3g 8mmol) is dissolved in DME (75mL), places three mouthfuls of round-bottomed flasks of 250mL with compound 5b, in this system, add aqueous sodium carbonate (2.6g, 8.3mL), vacuumize displacement nitrogen, add palladium (90mg successively, 0.4mmol), (210mg 0.8mmol), vacuumizes displacement nitrogen to triphenyl phosphorus again.Be warming up to 87 ℃ of heated and stirred 16h, be cooled to room temperature, add ethyl acetate (100mL) dilution, diatomite filtration, the ethyl acetate washing, filtrate is used the saturated common salt water washing, and the organic phase anhydrous magnesium sulfate drying filters, concentrate, silica gel column chromatography, ethyl acetate: sherwood oil=1: 1 is an eluent, obtains containing the crude product 1g of compound 6.
Crude product compound 6 is dissolved in the dioxane (100mL), and to wherein feeding hydrogen chloride gas, thin-layer chromatography is followed the trail of to compound 6 disappearances, concentrate, add water (25mL) dissolving, add yellow soda ash and transfer to PH=10, dichloromethane extraction, anhydrous magnesium sulfate drying filters, concentrate, column chromatography, methylene dichloride: methyl alcohol: triethylamine=10: 1: 0.1 concentrates the component that contains target compound, finally obtain target product deuterium Dai Keli azoles base of a fruit Buddhist nun (Crizotinib) I (330mg, white solid).
1H?NMR(400MHz，CDCl
3)δ1.84(s，3H)，1.90(m，2H)，2.15(m，2H)，2.77(m，2H)，3.23(m，2H)，4.21(m，1H)，4.76(br，2H)，6.87(d，J＝1.6Hz，1H)，7.08(dd，J＝8Hz，8.8Hz，1H)，7.32(dd，J＝4.8Hz，8.8Hz，1H)，7.50(s，1H)，7.76(s，1H)7.26(d，J＝1.6Hz，1H).
Embodiment 2:
Compound 1b (10g, 50.25mmol) be dissolved in anhydrous methanol (100mL), place the single necked round bottom flask of 250mL, room temperature, under the magnetic agitation, add in batches deuterium for sodium borohydride (3.8g, 100mmol), add the back that finishes and continue to stir 1h, add the 2mL shrend and go out, add 100mL water again, ethyl acetate extraction (150mL * 2) after concentrating, organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying filters, filtrate concentrate clear, colorless thickness oily product (leave standstill after a day and become white solid) compound 2b (9.6g, productive rate 95%).
1H?NMR(400MHz，CDCl
3)δ1.18(m，2H)，1.35(s，9H)，1.62(m，2H)，2.91(m，2H)，3.62(m，2H)，4.62(s，1H).
Compound 2b (9.6g 47.8mmol) is dissolved in methylene dichloride (120mL), places three mouthfuls of round-bottomed flasks of 250mL, add triethylamine (5g 48mmol), is cooled to 0 ℃, slowly drip methylsulfonyl chloride (5.5g, 47.8mmol), add DMAP (0.6g, 4.7mmol).Be warmed up to room temperature behind reinforced the finishing, continue to stir 3h, in reaction system, add entry (50mL), dichloromethane extraction, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, filtering and concentrating gets white solid compound 3b (13g, productive rate 98%).
1H?NMR(400MHz，CDCl
3)δ1.46(s，9H)，1.82(m，2H)，1.95(m，2H)，3.06(s，3H)3.31(m，2H)，3.71(m，2H).
(8.2g 42.4mmol) is dissolved in exsiccant DMF (150mL) to 4-iodo pyrazoles, places three mouthfuls of round-bottomed flasks of 250mL, and nitrogen atmosphere under 0 ℃, slowly adds sodium hydrogen (2g, 50.6mmol, content 60%) in batches.After reaction mixture continues down for 0 ℃ to stir 1h, add compound 3b, temperature of reaction rises to 120 ℃ and continuation stirring 12h, after the question response system temperature is reduced to room temperature, adds water (2mL) cancellation reaction, concentrate and remove most of DMF, add entry (100mL) then, ethyl acetate extraction (150mL * 2) merges organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying filters, and concentrates, use silica gel column chromatography, ethyl acetate: sherwood oil=1: 10 is an eluent, and the component that will contain compound 4b merges, and concentrates and obtains white solid, 25g, productive rate 79%.
1H?NMR(400MHz，CDCl
3)δ1.47(s，9H)，1.86(m，2H)，2.09(m，2H)，2.87(m，2H)，4.23(m，2H)，7.45(s，1H)，7.51(s，1H).
(5.2g 53.2mmol) places three mouthfuls of round-bottomed flasks of 250mL dewater (30mm, 180 ℃ to Potassium ethanoate, 10min), under the nitrogen atmosphere, add exsiccant DMF, (5g 13.3mmol), joins which alcohol ester (3.7g of borine Knit-the-brows to wherein adding compound 4b successively, 14.6mmol), palladium (150mg, 0.67mmol), triphenyl phosphorus (370mg, 1.4mmol), vacuumize displacement nitrogen after, be warming up to 80 ℃ and stir 2h.Reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing, concentrate remove most of DMF after, add entry (100mL) then, ethyl acetate extraction (150mL * 2), merge organic phase, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrate, use silica gel column chromatography, ethyl acetate: sherwood oil=1: 5 is an eluent, get the oily crude product, be directly used in next step.
Compound 1a (10g, 48.5mmol) be dissolved in anhydrous methanol (100mL), place the single necked round bottom flask of 250mL, room temperature, under the magnetic agitation, add in batches sodium borohydride (3g, 78mmol), add the back that finishes and continue to stir 1h, add the 2mL shrend and go out, add 100mL water again, ethyl acetate extraction (150mL * 2) after concentrating, organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying filters, filtrate concentrate clear, colorless thickness oily product (leave standstill after a day and become white solid) compound 2a (10g, productive rate 99%).
1H?NMR(400MHz，CDCl
3)δ1.65(d，J＝6.8Hz，3H)，2.90(d，J＝6.0Hz，1H)，5.59(m，1H)，7.03(t，J＝8.4Hz，1H)，7.27(t，J＝8.4Hz，1H).
Compound 2a splits through enzyme and obtains two optical isomer 2aR and 2aS.2aR is used for the synthetic of compound 3a.
Under the nitrogen atmosphere, triphenyl phosphorus (17.6g, 67.2mmol) and DEAD (11.7g, 67.2mmol) be dissolved in tetrahydrofuran (THF) (200mL), place three mouthfuls of round-bottomed flasks of 1L, be cooled to 0 ℃, under the magnetic agitation, (7.4g, 53mmol) (10g, tetrahydrofuran solution 48mmol) (200mL) joins in the round-bottomed flask by constant pressure funnel 3-hydroxyl-2-nitropyridine with compound 2aR.Resulting orange clear solution rises to stirring at room 3h, thin-layer chromatography shows that compound 2aR disappears, reaction solution is transferred in the 500mL single necked round bottom flask, concentrate, column chromatography, ethyl acetate: sherwood oil=1: 5 is an eluent, the component that will contain compound 3a merges, concentrate and obtain pink solid compound 3a (16g, productive rate 99%).
1H?NMR(400MHz，CDCl
3)δ1.86(d，J＝6.8Hz，3H)，6.10(q，J＝6.8Hz，1H)，7.09(d，J＝8.0Hz，8.8Hz，1H)，7.21(dd，J＝0.8Hz，8.4Hz，1H).7.32(dd，J＝4.8Hz，8.4Hz，1H)，7.38(dd，J＝4.8Hz，8.4Hz，1H)，8.04(dd，J＝0.8Hz，4.4Hz，1H).
In the round-bottomed flask of 2L, add acetic acid (900mL) successively, ethanol (700mL), compound 3a (16g, 48.5mmol), reduced iron powder (27g, 485mmol), slowly be heated to and reflux and maintenance backflow 1h, be cooled to concentrate after the room temperature and remove most of acetate and ethanol, add ethyl acetate (500mL) and water (500mL) then, in above-mentioned mixed system, slowly neutralize again as saturated sodium carbonate solution.((500mL * 2) merge organic phase to ethyl acetate extraction, use saturated sodium bicarbonate (200mL) successively, water (200mL), saturated aqueous common salt (200mL), washing, anhydrous magnesium sulfate drying, filter, concentrate and obtain pink solid compound 4a (13g, productive rate 90%).
1H?NMR(400MHz，CDCl
3)δ1.83(d，J＝6.4Hz，3H)，4.82(br，1H)，6.01(q，J＝6.8Hz，1H)，6.49(dd，J＝4.8Hz，7.6Hz，1H)，6.71(dd，J＝1.2Hz，8.0Hz，1H).7.05(dd，J＝7.6Hz，8.4Hz，1H)，7.30(dd，J＝4.8Hz，8.8Hz，1H)，7.61(dd，J＝1.2Hz，5.2Hz，1H).
(13g 43.3mmol) is dissolved in the round-bottomed flask that acetonitrile (150mL) places 250mL to compound 4a, is cooled to 0 ℃, and (7.8g 43.3mmol) slowly adds NBS in batches, and adding finishes back 0 ℃ continues to stir 30min down.Reaction solution is concentrated, column chromatography, ethyl acetate: sherwood oil=1: 1 be an eluent, and the component that will contain compound 5a merges, the concentrated brown solid compound 5a (9g, productive rate 55%) that obtains.
1HNMR(400MHz，CDCl
3)δ1.81(d，J＝6.8Hz，3H)，4.82(br，1H)，5.97(q，J＝6.4Hz，1H)，6.83(d，J＝1.6Hz，1H)，7.08(t，J＝8.0Hz，1H)，7.31(dd，J＝4.8Hz，8.8Hz，1H)，7.65(d，J＝1.6Hz，1H)
Compound 5a (2.6g, 7mmol) (3g 8mmol) is dissolved in DME (75mL), places three mouthfuls of round-bottomed flasks of 250mL with compound 5b, in this system, add aqueous sodium carbonate (2.6g, 8.3mL), find time to change nitrogen, add palladium (90mg successively, 0.4mmol), (210mg 0.8mmol), vacuumizes displacement nitrogen to triphenyl phosphorus again.Be warming up to 87 ℃ of heated and stirred 16h, be cooled to room temperature, add ethyl acetate (100mL) dilution, diatomite filtration, the ethyl acetate washing, filtrate is used the saturated common salt water washing, and the organic phase anhydrous magnesium sulfate drying filters, concentrate, silica gel column chromatography, ethyl acetate: sherwood oil=1: 1 is an eluent, obtains containing the crude product (1g) of compound 6.
Crude product compound 6 is dissolved in the dioxane (100mL), and to wherein feeding hydrogen chloride gas, thin-layer chromatography is followed the trail of to compound 6 disappearances, concentrate, add water (25mL) dissolving, add yellow soda ash and transfer to PH=10, dichloromethane extraction, anhydrous magnesium sulfate drying filters, concentrate, column chromatography, methylene dichloride: methyl alcohol: triethylamine=10: 1: 0.1 concentrates the component that contains target compound, finally obtain target product deuterium Dai Keli azoles base of a fruit Buddhist nun (Crizotinib) II (330mg, white solid).δ1.85(d，J＝6.8Hz，3H)，1.97(m，2H)，2.18(m，2H)，2.78(m，2H)，3.27(m，2H)，479(br，1H)，6.08(q，J＝6.0Hz，1H)，6.87(d，J＝1.6Hz，1H)，7.05(t，J＝8.0Hz，1H)，7.31(dd，J＝4.8Hz，8.8Hz，1H)，7.51(s，1H)，7.56(s，1H)，7.76(d，J＝1.6Hz，1H)
Claims (10)
1. deuterium Dai Keli azoles base of a fruit Buddhist nun and derivative thereof, its structural formula is as (I) or (II):
Wherein, R is hydrogen or tert-butoxycarbonyl.
2. the intermediate of preparation deuterium Dai Keli azoles base of a fruit Buddhist nun and derivative process thereof is characterized in that, shown in 5a or 5b:
3. the preparation method of the described deuterium Dai Keli of claim 1 azoles base of a fruit Buddhist nun and derivative thereof; it is characterized in that; be dissolved in N earlier with the formula 5b compound in formula 5a compound and non-deuterium generation or with the formula 5a compound and the formula 5b compound in non-deuterium generation; dinethylformamide (DMF); diethylformamide (DMA); dioxane or triethylamine; add yellow soda ash afterwards; salt of wormwood; Potassium ethanoate or triethylamine; under the nitrogen protection; add palladium successively; triphenyl phosphorus; be warming up to 60-150 ℃ of heated and stirred 2-24h, be cooled to room temperature, obtain deuterium Dai Keli azoles base of a fruit Buddhist nun derivative after the conventional aftertreatment.
4. the preparation method of deuterium Dai Keli azoles base of a fruit Buddhist nun as claimed in claim 3 and derivative thereof, it is characterized in that, described deuterium Dai Keli azoles base of a fruit Buddhist nun derivative is dissolved in the organic solvent, to wherein feeding hydrogen chloride gas, monitor when derivative disappears, concentrate, it be alkaline transferring PH, conventional afterwards aftertreatment obtains deuterium Dai Keli azoles base of a fruit Buddhist nun.
5. the preparation method of the intermediate formula 5a compound of the described preparation deuterium of claim 2 Dai Keli azoles base of a fruit Buddhist nun and derivative process thereof, it is characterized in that, step is as follows: add acetic acid in reaction vessel successively, ethanol, formula 3a compound, reduced iron powder, slowly be heated to and reflux and maintenance backflow 0-5h, be cooled to concentrate after the room temperature and remove most of solvent, add isopyknic ethyl acetate and water then, slowly inject the saturated sodium carbonate solution neutralization again in above-mentioned mixed system, conventional aftertreatment concentrates and obtains formula 4a compound, wherein the mole dosage of raw material reduced iron powder be formula 3a compound 8-20 doubly; Compound 4a is dissolved in the acetonitrile, cooling, N-bromosuccinimide slowly adds in batches, cooling continues to stir conventional afterwards aftertreatment, column chromatography down, obtain formula 5a compound, wherein the N-bromosuccinimide mole dosage be formula 4a compound 0.6-3.0 doubly;
6. the preparation method of the intermediate formula 5a compound of preparation deuterium Dai Keli azoles base of a fruit Buddhist nun as claimed in claim 5 and derivative process thereof, it is characterized in that, the preparation method of formula 3a compound is as follows: under the nitrogen atmosphere, triphenyl phosphorus and DEAD are dissolved in tetrahydrofuran (THF), dioxane, N, in dinethylformamide, diethylamide, dioxane or the triethylamine, be cooled to 0 ℃, under the magnetic agitation, the tetrahydrofuran solution of 3-hydroxyl-2-nitropyridine and compound 2aR adds by constant pressure funnel; Resulting orange clear solution rises to stirring at room, and thin-layer chromatography shows that compound 2aR disappears, and conventional aftertreatment concentrates and obtains solid chemical compound 3a; The amount of substance ratio that wherein feeds intake is: 2aR: triphenyl phosphorus: DEAD: 3-hydroxyl-2-nitropyridine is 1: 1-3: 1-3: 1-3;
7. the preparation method of the intermediate formula 5a compound of preparation deuterium Dai Keli azoles base of a fruit Buddhist nun as claimed in claim 6 and derivative process thereof, it is characterized in that, the preparation method of formula 2aR compound is as follows: the reductive agent in formula 1a compound and deuterium generation is dissolved in room temperature reaction in the organic solvent, obtain formula 2a compound, compound 2a is split through enzyme obtain optical isomer 2aR and 2aS; Wherein the reductive agent in deuterium generation is meant the deuterium lithium aluminium hydride (LiAlD in generation
4), the sodium borohydride (NaBD in deuterium generation
4), the acetic acid sodium borohydride (NaB (OAc) in deuterium generation
3D) and the sodium cyanoborohydride (NaBCND in deuterium generation
3) in a kind of, organic solvent is meant a kind of in benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, dioxane, the trichloromethane;
8. the preparation method of the intermediate formula 5b compound of the described preparation deuterium of claim 2 Dai Keli azoles base of a fruit Buddhist nun and derivative process thereof is characterized in that step is as follows:
4-iodo pyrazoles is dissolved in exsiccant N, dinethylformamide, diethylamide, dioxane, in tetrahydrofuran (THF) or the toluene, nitrogen atmosphere, under 0 ℃, slowly adding total mole dosage in batches is 4-iodo pyrazoles 1.0-3.0 sodium hydrogen doubly; Reaction mixture-10 ℃ adds compound 3b after continuing down to stir to 10 ℃, and temperature of reaction rises to 60-120 ℃ and continue to stir, and after the question response system temperature is reduced to room temperature, adds the shrend reaction of going out, the concentrated compound 4b that obtains of conventional aftertreatment;
Under the nitrogen atmosphere, Potassium ethanoate is added exsiccant N, in dinethylformamide, diethylamide, dioxane, tetrahydrofuran (THF) or the toluene, to wherein adding formula 4b compound, connection borine Knit-the-brows is which alcohol ester successively, palladium, triphenyl phosphorus is warming up to 80-150 ℃ and stirs 1-24h, and reaction system is cooled to room temperature, diatomite filtration, conventional aftertreatment gets the 5b compound; The amount of substance ratio that feeds intake is: formula 4b compound: Potassium ethanoate: connection borine Knit-the-brows is which alcohol ester: palladium, triphenyl phosphorus are 1: 1-5: 0.8-2.0: 0.01-0.15: 0.01-0.4;
9. the preparation method of the intermediate formula 5b compound of preparation deuterium Dai Keli azoles base of a fruit Buddhist nun as claimed in claim 8 and derivative process thereof, it is characterized in that, the preparation process of formula 3b compound is as follows: the reductive agent in 1b and deuterium generation is dissolved in room temperature reaction in the organic solvent, obtains compound 2b; Wherein the reductive agent in deuterium generation is meant the deuterium lithium aluminium hydride (LiAlD in generation
4), the sodium borohydride (NaBD in deuterium generation
4), the acetic acid sodium borohydride (NaB (OAc) in deuterium generation
3D) and the sodium cyanoborohydride (NaBCND in deuterium generation
3) in a kind of, organic solvent is meant a kind of in benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or the ethanol;
Compound 2b is dissolved in methylene dichloride, benzene, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or the ethanol, adds organic amine, be cooled to-10 to 10 ℃, slowly drip methylsulfonyl chloride, add N, N-dimethyl aminopyridine (DMAP); Be warmed up to room temperature behind reinforced the finishing, continue to stir 1-8h, in reaction system, add entry and get compound 3b through conventional aftertreatment; The amount of substance ratio that feeds intake is: 2b: organic amine: methylsulfonyl chloride: DMAP is 1: 1-5: 1-5: 0.01-0.25;
10. the application of the described deuterium Dai Keli of claim 1 azoles base of a fruit Buddhist nun aspect preparation treatment cancer drug.
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| CN102079744A (en) | 2011-06-01 |
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