CN102079744B - Deuterated achiral crizotinib and derivatives, preparation method and application thereof - Google Patents
Deuterated achiral crizotinib and derivatives, preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of synthesis of medicinal compounds and in particular relates to deuterated achiral crizotinib and a preparation method and application thereof. Deuterated derivatives of the achiral crizotinib have medicament effects similar to the crizotinib, so that novel compounds for synthesizing novel antineoplastic medicaments are provided and a novel approach for synthesizing the antineoplastic medicaments is developed.
Description
Technical field
The invention belongs to the synthetic field of pharmaceutical compound, particularly deuterium is for achirality Crizotinib and derivative thereof, preparation method and application.
Background technology
Nonsmall-cell lung cancer is modal Lung Cancer Types, accounts for 80% to 85% of all patients with lung cancer, and wherein some patients were is attended by transgenation.Genic mutation type Patients with Non-small-cell Lung 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.
Crizotinib (Crizotinib) by the research and development of Pfizer pharmaceutical Co. Ltd can effectively dwindle late gene saltant type nonsmall-cell lung cancer (NSCLC) patient's malignant tumour size through clinical verification.One clinical trial phase confirmation, Crizotinib tells on to 90% late gene saltant type Patients with Non-small-cell Lung, and wherein 8 weeks rear tumours of patient's oral pharmaceutical of 57% 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 acted on of malignant tumour and preparation method thereof becomes the development of new antitumor drug.
Summary of the invention
The object of the present invention is to provide a kind of deuterium for achirality Crizotinib and derivative thereof, preparation method and application, in deuterium generation, carried out in two positions in Crizotinib (Crizotinib) structure, for the synthesizing new antitumor drug provides new compound, also for antitumor drug synthetic, open up new approach.
The technical solution used in the present invention is as follows:
Deuterium is for achirality Crizotinib and derivative thereof, and its structural formula is as (I) or (II):
Wherein, R is hydrogen or tert-butoxycarbonyl.
The present invention also provides and has prepared the intermediate of achirality deuterium for Crizotinib and derivative thereof, suc as formula
5aor
5bshown in:
Described deuterium for the preparation method of the derivative of achirality Crizotinib is, by formula
5athe formula 5b compound in compound and non-deuterium generation or by the non-deuterium formula in generation
5acompound and formula
5bcompound first is dissolved in DMF (DMF), diethylamide (DMA), dioxane or triethylamine, adds afterwards sodium carbonate, salt of wormwood, Potassium ethanoate or triethylamine; under nitrogen protection; add successively palladium, triphenyl phosphorus, be warming up to 60-150 ℃ of heated and stirred 2-24h, be cooled to room temperature; add the ethyl acetate dilution; filter, drying, concentrated; silica gel column chromatography separates, and obtains deuterium for achirality Crizotinib derivative.
Further, described deuterium is dissolved in organic solvent for achirality Crizotinib derivative, pass into wherein hydrogen chloride gas, monitor while disappearing to derivative, concentrated, adjusting PH is alkalescence, and conventional aftertreatment afterwards can obtain deuterium for the achirality Crizotinib, and described organic solvent can be selected dioxane or tetrahydrofuran (THF).
Formula
5athe preparation method of compound is as follows:
By formula
1athe reductive agent in compound and deuterium generation is dissolved in room temperature reaction in organic solvent, obtains formula
2acompound; Wherein the reductive agent in deuterium generation can be selected 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) or the sodium cyanoborohydride (NaBCND in deuterium generation
3), organic solvent is benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, dioxane or trichloromethane; Formula
1astructural formula of compound is as follows:
Under nitrogen atmosphere, triphenyl phosphorus and diethyl azodiformate DEAD are dissolved in tetrahydrofuran (THF), dioxane, DMF, diethylamide, dioxane or triethylamine, are cooled to 0
oc, under magnetic agitation, the tetrahydrofuran solution of 3-hydroxyl-2-nitropyridine and formula 2a compound adds by constant pressure funnel; The orange clear solution obtained rises to stirring at room, and thin-layer chromatography display type 2a compound disappears, conventional aftertreatment, the concentrated solid type 3a compound that obtains; The amount of substance ratio that wherein feeds intake is: formula 2a compound: triphenyl phosphorus: DEAD:3-hydroxyl-2-nitropyridine is 1:1-3:1-3:1-3;
Add successively acetic acid, ethanol, formula in reaction vessel
3acompound, reduced iron powder, slowly be heated to reflux and keep backflow to be no more than 5h, be cooled to and concentratedly after room temperature remove half to 2/3rds solvent, then add the isopyknic mixture of ethyl acetate and water, slowly inject the saturated sodium carbonate solution neutralization again in above-mentioned mixed system, the concentrated formula that obtains of conventional aftertreatment
4acompound, wherein the amount of substance of reduced iron powder is formula
3athe 8-20 of compound doubly; By compound
4abe dissolved in acetonitrile, cooling, N-bromosuccinimide slowly adds in batches, and cooling lower continuation is stirred, conventional aftertreatment afterwards, and column chromatography, obtain formula
5acompound, wherein the N-bromosuccinimide amount of substance is formula
4athe 0.6-3.0 of compound doubly; Formula 3a compound, formula 4a structural formula of compound are as follows:
Described intermediate formula
5bthe preparation method of compound is as follows:
Will
1bbe dissolved in room temperature reaction in organic solvent with the reductive agent in deuterium generation, obtain formula
2bcompound; Wherein the reductive agent in deuterium generation is 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) or the sodium cyanoborohydride (NaBCND in deuterium generation
3), organic solvent is benzene, methylene dichloride, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or ethanol.
Formula 2b compound is dissolved in methylene dichloride, benzene, acetonitrile, tetrahydrofuran (THF), toluene, methyl alcohol or ethanol, adds organic amine, be cooled to-10 to 10
oc, slowly drip methylsulfonyl chloride, adds N, N-dimethyl aminopyridine (DMAP); Be warmed up to room temperature after reinforced, continue to stir 1-8h, in reaction system, add water and obtain formula 3b compound through conventional aftertreatment; The amount of substance ratio that feeds intake is: formula 2b compound: organic amine: methylsulfonyl chloride: DMAP is 1:1-5:1-5:0.01-0.25;
4-iodo pyrazoles is dissolved in dry DMF, diethylamide, dioxane, tetrahydrofuran (THF) or toluene to nitrogen atmosphere, 0
ounder C, slowly adding in batches total amount of substance is 4-iodo pyrazoles 1.0-3.0 sodium hydride doubly; Reaction mixture-10
oc to 10
oafter continuing under C to stir, add formula
3bcompound, temperature of reaction rises to 60-120
oc also continue to stir, and after the question response system temperature is down to room temperature, adds the shrend reaction of going out, and conventional aftertreatment concentrates the formula that obtains
4bcompound
;
Under nitrogen atmosphere, Potassium ethanoate is added in dry DMF, diethylamide, dioxane, tetrahydrofuran (THF) or toluene, add wherein successively formula
4bcompound, which alcohol ester of connection borine Knit-the-brows, palladium, triphenyl phosphorus, be warming up to 80-150 ℃ and stir 1-24h, and reaction system is cooled to room temperature, diatomite filtration, and conventional aftertreatment obtains formula
5bcompound; The amount of substance ratio that feeds intake is: formula
4bcompound: Potassium ethanoate: connection borine Knit-the-brows is which alcohol ester: palladium: triphenyl phosphorus is 1:1-5:0.8-2.0:0.01-0.15:0.01-0.4; Formula
3bcompound, formula
4bthe structural formula of compound is as follows:
Described deuterium is having good application prospect for the achirality Crizotinib aspect preparation treatment cancer drug.
Lung cancer particularly.
The deuterium of synthesized of the present invention has the biological activity similar to Crizotinib (Crizotinib) for achirality Crizotinib (Crizotinib) and derivative thereof, and the target spot of effect is all a modification lymphoma kinases ALK(Anaplastic Lymphoma Kinase).
The present invention, with respect to prior art, has following advantage:
Achirality Crizotinib provided by the present invention (Crizotinib) deuterium has the drug effect similar to Crizotinib (Crizotinib) for derivative, thereby, for the synthesizing new antitumor drug provides new compound, also for the synthetic of antitumor drug, open up a new way.
Embodiment
Below with specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to this:
Embodiment 1
Compound
1b(10g, 50.25mmol) be dissolved in anhydrous methanol (100mL), be placed in the single necked round bottom flask of 250mL, room temperature, under magnetic agitation, add in batches sodium borohydride (3.8g, 100mmol), continue to stir 1h after adding, add the 2mL shrend to go out, add again 100mL water after concentrated, ethyl acetate extraction (150mL * 2), organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying, filter, and filtrate concentrates to obtain clear, colorless thickness oily product (after standing a day, becoming 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), is placed in tri-mouthfuls of round-bottomed flasks of 250mL, adds triethylamine (5g, 48mmol), is cooled to 0
oc, slowly drip methylsulfonyl chloride (5.5g, 47.8mmol), adds DMAP(0.6g, 4.7mmol).Be warmed up to room temperature after reinforced, continue to stir 3h, in reaction system, add water (50mL), dichloromethane extraction, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, filtering and concentrating obtains the 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).
4-iodo pyrazoles (8.2g, 42.4mmol) is dissolved in dry DMF(150mL), be placed in three mouthfuls of round-bottomed flasks of 250mL, nitrogen atmosphere, 0
ounder C, slowly add in batches sodium hydride (2g, 50.6mmol, content 60%).Reaction mixture 0
oafter continuing under C to stir 1h, add compound
3b, temperature of reaction rises to 120
oc also continues to stir 12h, after the question response system temperature is down to room temperature, adds water (2mL) cancellation reaction, concentrate and remove most of DMF, then add water (100mL), ethyl acetate extraction (150mL * 2), merge organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrated, use silica gel column chromatography, ethyl acetate: sherwood oil=1:10 is eluent, will contain compound
4bcomponent merge, the concentrated white solid compound that obtains
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).
Potassium ethanoate (5.2g, 53.2mmol) is placed in tri-mouthfuls of round-bottomed flasks of 250mL dewater (30mm, 180
oc, 10min), under nitrogen atmosphere, add dry DMF, add wherein successively compound
4b(5g, 13.3mmol), connection borine Knit-the-brows is which alcohol ester (3.7g, 14.6mmol), palladium (150mg, 0.67mmol), triphenyl phosphorus (370mg, 1.4mmol), after vacuumizing displacement nitrogen, be warming up to 80
oc stirs 2h.Reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing, concentrated remove most of DMF after, then add water (100mL), ethyl acetate extraction (150mL * 2), merge organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrated, use silica gel column chromatography, ethyl acetate: sherwood oil=1:5 is eluent, will contain compound
5bcomponent merge, the concentrated white solid compound that obtains
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), be placed in the single necked round bottom flask of 250mL, room temperature, under magnetic agitation, add in batches deuterium for sodium borohydride (3g, 78mmol), continue to stir 1h after adding, add the 2mL shrend to go out, add again 100mL water 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 concentrates to obtain clear, colorless thickness oily product (after standing a day, becoming 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).
Under nitrogen atmosphere, triphenyl phosphorus (17.6g, 67.2mmol) and DEAD(11.7g, 67.2mmol) be dissolved in tetrahydrofuran (THF) (200mL), be placed in three mouthfuls of round-bottomed flasks of 1L, be cooled to 0
oc, under magnetic agitation, 3-hydroxyl-2-nitropyridine (7.4g, 53mmol) and compound
2athe tetrahydrofuran solution of (10g, 48mmol) (200mL) joins in round-bottomed flask by constant pressure funnel.Resulting orange clear solution rises to stirring at room 3h, and thin-layer chromatography shows compound
2adisappear, reaction solution is transferred in the 500mL single necked round bottom flask, concentrated, column chromatography, ethyl acetate: sherwood oil=1:5 is eluent, will contain compound
3acomponent merge, the concentrated pink solid compound that obtains
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).
Add successively acetic acid (900mL) in the round-bottomed flask of 2L, ethanol (700mL), compound
3a(16g, 48.5mmol), reduced iron powder (27g, 485mmol), slowly be heated to reflux and keep backflow 1h, be cooled to and concentratedly after room temperature remove most of acetic acid and ethanol, then add ethyl acetate (500mL) and water (500mL), more slowly add saturated sodium carbonate solution to neutralize in above-mentioned mixed system.Ethyl acetate extraction (500mL * 2), merge organic phase, uses successively saturated sodium bicarbonate (200mL), water (200mL), and saturated aqueous common salt (200mL), washing, anhydrous magnesium sulfate drying, filter, the concentrated compound that obtains
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).
Compound
4a(13g, 43.3mmol) is dissolved in the round-bottomed flask that acetonitrile (150mL) is placed in 250mL, is cooled to 0
oc, NBS(7.8g, 43.3mmol) slowly add in batches, after interpolation 0
ocontinue to stir 30min under C.Reaction solution is concentrated, column chromatography, ethyl acetate: sherwood oil=1:1 is eluent, will contain compound
5acomponent merge, the concentrated brown solid compound that obtains
5a(9g, productive rate 55%).
1H NMR(400MHz, CDCl
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) and compound
5b(3g, 8mmol) be dissolved in DME(75mL), be placed in three mouthfuls of round-bottomed flasks of 250mL, in this system, add aqueous sodium carbonate (2.6g, 8.3mL), vacuumize displacement nitrogen, add successively palladium (90mg, 0.4mmol), triphenyl phosphorus (210mg, 0.8mmol), then vacuumize displacement nitrogen.Be warming up to 87
oc 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, concentrated, silica gel column chromatography, ethyl acetate: sherwood oil=1:1 is eluent, obtains containing compound
6crude product 1g.
By the crude product compound
6be dissolved in dioxane (100mL), pass into wherein hydrogen chloride gas, thin-layer chromatography is followed the trail of to compound
6disappear, concentrated, add water (25mL) and dissolve, add sodium carbonate to be adjusted to PH=10, dichloromethane extraction, anhydrous magnesium sulfate drying, filter, concentrated, column chromatography, methylene dichloride: methyl alcohol: triethylamine=10:1:0.1, the concentrated component that contains target compound, finally obtain the target product deuterium for achirality Crizotinib (Crizotinib) formula I compound (R is H) (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), be placed in the single necked round bottom flask of 250mL, room temperature, under magnetic agitation, add in batches deuterium for sodium borohydride (3.8g, 100mmol), continue to stir 1h after adding, add the 2mL shrend to go out, add again 100mL water after concentrated, ethyl acetate extraction (150mL * 2), organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying, filter, and filtrate concentrates to obtain clear, colorless thickness oily product (after standing a day, becoming 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), is placed in tri-mouthfuls of round-bottomed flasks of 250mL, adds triethylamine (5g, 48mmol), is cooled to 0
oc, slowly drip methylsulfonyl chloride (5.5g, 47.8mmol), adds DMAP(0.6g, 4.7mmol).Be warmed up to room temperature after reinforced, continue to stir 3h, in reaction system, add water (50mL), dichloromethane extraction, organic phase saturated common salt water washing, anhydrous magnesium sulfate drying, filtering and concentrating obtains the 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).
4-iodo pyrazoles (8.2g, 42.4mmol) is dissolved in dry DMF(150mL), be placed in three mouthfuls of round-bottomed flasks of 250mL, nitrogen atmosphere, 0
ounder C, slowly add in batches sodium hydride (2g, 50.6mmol, content 60%).Reaction mixture 0
oafter continuing under C to stir 1h, add compound
3b, temperature of reaction rises to 120
oc also continues to stir 12h, after the question response system temperature is down to room temperature, adds water (2mL) cancellation reaction, concentrate and remove most of DMF, then add water (100mL), ethyl acetate extraction (150mL * 2), merge organic phase, the saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrated, use silica gel column chromatography, ethyl acetate: sherwood oil=1:10 is eluent, will contain compound
4bcomponent merge, concentratedly obtain 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).
Potassium ethanoate (5.2g, 53.2mmol) is placed in tri-mouthfuls of round-bottomed flasks of 250mL dewater (30mm, 180
oc, 10min), under nitrogen atmosphere, add dry DMF, add wherein successively compound
4b(5g, 13.3mmol), connection borine Knit-the-brows is which alcohol ester (3.7g, 14.6mmol), palladium (150mg, 0.67mmol), triphenyl phosphorus (370mg, 1.4mmol), after vacuumizing displacement nitrogen, be warming up to 80
oc stirs 2h.Reaction system is cooled to room temperature, diatomite filtration, ethyl acetate washing, concentrated remove most of DMF after, then add water (100mL), ethyl acetate extraction (150mL * 2), merge organic phase, saturated common salt water washing, anhydrous magnesium sulfate drying, filter, concentrated, use silica gel column chromatography, ethyl acetate: sherwood oil=1:5 is eluent, obtain the oily crude product, be directly used in next step.
Compound
1a(10g, 48.5mmol) be dissolved in anhydrous methanol (100mL), be placed in the single necked round bottom flask of 250mL, room temperature, under magnetic agitation, add in batches sodium borohydride (3g, 78mmol), continue to stir 1h after adding, add the 2mL shrend to go out, add again 100mL water after concentrated, ethyl acetate extraction (150mL * 2), organic phase is used saturated aqueous common salt (100mL) successively, water (100mL) washing, anhydrous magnesium sulfate drying, filter, and filtrate concentrates to obtain clear, colorless thickness oily product (after standing a day, becoming 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).
Under nitrogen atmosphere, triphenyl phosphorus (17.6g, 67.2mmol) and DEAD(11.7g, 67.2mmol) be dissolved in tetrahydrofuran (THF) (200mL), be placed in three mouthfuls of round-bottomed flasks of 1L, be cooled to 0
oc, under magnetic agitation, 3-hydroxyl-2-nitropyridine (7.4g, 53mmol) and compound
2athe tetrahydrofuran solution of (10g, 48mmol) (200mL) joins in round-bottomed flask by constant pressure funnel.Resulting orange clear solution rises to stirring at room 3h, and thin-layer chromatography shows compound
2adisappear, reaction solution is transferred in the 500mL single necked round bottom flask, concentrated, column chromatography, ethyl acetate: sherwood oil=1:5 is eluent, will contain compound
3acomponent merge, the concentrated pink solid compound that obtains
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).
Add successively acetic acid (900mL) in the round-bottomed flask of 2L, ethanol (700mL), compound
3a(16g, 48.5mmol), reduced iron powder (27g, 485mmol), slowly be heated to reflux and keep backflow 1h, be cooled to and concentratedly after room temperature remove most of acetic acid and ethanol, then add ethyl acetate (500mL) and water (500mL), more slowly add saturated sodium carbonate solution to neutralize in above-mentioned mixed system.Ethyl acetate extraction (500mL * 2), merge organic phase, uses successively saturated sodium bicarbonate (200mL), water (200mL), and saturated aqueous common salt (200mL), washing, anhydrous magnesium sulfate drying, filter, the concentrated pink solid compound that obtains
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, 5.2 Hz, 1H).
Compound
4a(13g, 43.3mmol) is dissolved in the round-bottomed flask that acetonitrile (150mL) is placed in 250mL, is cooled to 0
oc, NBS(7.8g, 43.3mmol) slowly add in batches, after interpolation 0
ocontinue to stir 30min under C.Reaction solution is concentrated, column chromatography, ethyl acetate: sherwood oil=1:1 is eluent, will contain compound
5acomponent merge, the concentrated brown solid compound that obtains
5a(9g, productive rate 55%).
1H NMR(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) and compound
5b(3g, 8mmol) is dissolved in DME(75mL), be placed in three mouthfuls of round-bottomed flasks of 250mL, add aqueous sodium carbonate (2.6g in this system, 8.3mL), find time to change nitrogen, add successively palladium (90mg, 0.4mmol), triphenyl phosphorus (210mg, 0.8mmol), then vacuumize displacement nitrogen.Be warming up to 87
oc 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, concentrated, silica gel column chromatography, ethyl acetate: sherwood oil=1:1 is eluent, obtains containing compound
6crude product (1g).
By the crude product compound
6be dissolved in dioxane (100mL), pass into wherein hydrogen chloride gas, thin-layer chromatography is followed the trail of to compound
6disappear, concentrated, add water (25mL) and dissolve, add sodium carbonate to be adjusted to PH=10, dichloromethane extraction, anhydrous magnesium sulfate drying, filter, concentrated, column chromatography, methylene dichloride: methyl alcohol: triethylamine=10:1:0.1, the concentrated component that contains target compound, finally obtain the target product deuterium for achirality Crizotinib (Crizotinib) formula II compound (R is hydrogen) (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)
bioactive mensuration
purpose: use the Km value research under different Triphosadens (ATP) concentration of Caliper Mobility Shift Assay method to screen the activity of modification lymphoma kinases (ALK) between formula I compound and formula II compound pair.
technical background: use Caliper Mobility Shift Assay method external activity of modification lymphoma (ALK) between screening type I compound and formula II compound (R is all hydrogen) pair under ATP Km concentration, and use staurosporine (Staurosporine) to make reference substance, the bioactivity screening of compound will be under 10 concentration replication.
material:
Between modification lymphoma kinases (ALK) (Carna, Cat.No.08-105, Lot. No. 08CBS-0112)
Peptide FAM-P22 (GL Biochem, Cat. No.112393, Lot. No. P080401-XY112393)
Adenosine triphyosphate ATP (Sigma, Cat.No.A7699-1G, CAS No.987-65-5)
Methyl-sulphoxide (DMSO) (Sigma, Cat.No.D2650, Lot. No.474382)
Ethylenediamine tetraacetic acid (EDTA) (EDTA) (Sigma, Cat.No.E5134, CAS No.60-00-4)
96-hole test panel (Lot.No. 22008026 for Corning company, Cat.3365)
384-hole test panel (Lot.No. 12608008 for Corning company, Cat.3573)
Staurosporine (Staurosporine) (Sigma, Cat.No.S4400-1MG, Lot.No.046K4080)
given the test agent
Sample
deuterium is formula I compound for the achirality Crizotinibwith
formula II compoundweigh respectively 1.58 milligrams and 1.52 milligrams and dissolve in methyl-sulphoxide (DMSO), be made into the solution that concentration is 10mM.
experimental technique
1. prepare the basic buffered soln of kinases and the cancellation buffered soln of 1.25x with kinases for experiment.
1. not containing manganous chloride (MnCl
2) the 1.25x kinases
basic buffered soln
Hydroxyethyl piperazine second thiosulfonic acid (HEPES) solution that concentration is 62.5mM, pH=7.5
The Brij-35 that mass body volume concentrations (mass unit is g, and volume unit is L, lower same) is 0.001875%
Magnesium dichloride (the MgCl that concentration is 12.5mM
2) solution
The dithiothreitol (DTT) that concentration is 2.5mM (DTT) solution
2. containing manganous chloride (MnCl
2) the 1.25x kinases
basic buffered soln
The HEPES solution that concentration is 62.5mM, pH=7.5
The Brij-35 that the mass body volume concentrations is 0.001875%
Magnesium dichloride (the MgCl that concentration is 12.5mM
2) solution
Manganous chloride (the MnCl that concentration is 12.5mM
2) solution
The dithiothreitol (DTT) that concentration is 2.5mM (DTT) solution
3. cancellation
buffered soln
The HEPES solution that concentration is 100mM, pH=7.5
The Brij-35 that the mass body volume concentrations is 0.015%
The coating-#3 reagent(3 surface reagent that the mass body volume concentrations is 0.2%, Caliper company product)
The EDTA solution that concentration is 50mM
II.
for experiment is prepared compound with kinases
series of compounds (continuously) dilution
4. draw formula I and the formula II compound solution that 5 microlitre concentration are 10mM and be transferred in test tube, add 95 microlitre DMSO, being diluted to compound concentration is 500 μ M
5. the compound in test tube is transferred to the wherein hole in the storage disks of 96-hole, wherein 30 μ L transfer in next adjacent holes, and add the DMSO dilution of 60 μ L, with this method serial dilution, obtain 10 compound solutions of concentration from 500 μ M to 0.025 μ M.
6. in the test board in same 96-hole, all add the DMSO of 60 μ L in each round, be DMSO and control.
7. get 5 μ L solution and be transferred in the test panel in another 96 hole from each hole, and add the H of 45 μ L
2o.
8. the EDTA that shifts 70 μ L250mM does low control.
9. getting 5 μ L in each hole is transferred in the analysis disc of 384-hole.Contain the low A1 controlled in the 96-porose disc and transfer to A1 and the A2 in the 384-porose disc, will proceed to A3 and the A4 of 384-porose disc in the 96-porose disc containing the A2 of maximum compound concentration, by that analogy.(label that A1-A4 is hole)
Like this, just contain the 10%DMSO solution of 5x compound in this analysis disc, the initial concentration of compound is 50 μ M.
kinase reaction
1) prepare the 2.5x enzyme solution
10. kinases is added to the kinases of 1.25x
basic buffered soln
2)
prepare the 2.5x peptide solution
11. the peptide of FAM-mark and ATP are joined to 1.25 kinases
basic buffered soln
3) the 2.5x enzyme solution is transferred in analysis disc
12. in analysis disc, have now the 10%DMSO solution of the compound of 5 μ L
13. add 10 μ L 2.5x enzyme solution in each hole of 384-hole analysis disc.
14. at room temperature hatch 10 minutes
4) the 2.5x peptide solution is proceeded in analysis disc
15. add 10 μ L 2.5x peptide solutions in each hole of 384-hole analysis disc.
) enzyme reaction and cancellation
16. 28
ounder C, hatching is 1 hour.
17. add 25 μ L cancellation buffered soln with stopped reaction.
) the Caliper reading of data
18. Caliper collects data
7) fitting of a curve
19. copies data from Caliper
20. change conversion values into inhibiting value
Inhibition percentage=(maximum value-conversion values)/(maximum value-minimum value) * 100
Maximum value represents that DMSO controls (DMSO control); Low control (the low control) of minimum value representative
21. fitting data is to obtain the IC50 value in Xlfit
Use following equation:
Y=minimum value+(maximum value-minimum value)/(1+10^ ((LogIC50-X) * slope))
（Y= Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))）
experimental result
the active IC50(nM of the inhibition of modification lymphoma kinases (ALK) between given the test agent pair) value
conclusion:
Screen by Bioactivity, take staurosporine as reference substance, between the formula I compound of our synthesized and formula II compound pair, modification lymphoma kinases (ALK) all has very strong inhibition ability, and IC50(nM) value is respectively 14.9 and 9.5.
Claims (4)
1. deuterium is for achirality Crizotinib and derivative thereof, and its structural formula is as (I) or (II):
Wherein, R is hydrogen or tert-butoxycarbonyl.
2. deuterium claimed in claim 1, for the preparation method of the derivative of achirality Crizotinib, is characterized in that, by the formula 5b compound in formula 5a compound and non-deuterium generation or by the non-deuterium formula in generation
5acompound and formula
5bcompound first is dissolved in N, dinethylformamide, diethylamide, dioxane or triethylamine, add afterwards sodium carbonate, salt of wormwood, Potassium ethanoate or triethylamine, under nitrogen protection, add successively palladium, triphenyl phosphorus, be warming up to 60-150 ℃ of heated and stirred 2-24h, be cooled to room temperature, obtain the derivative of deuterium for the achirality Crizotinib after conventional aftertreatment;
3. deuterium claimed in claim 1, for the preparation method of achirality Crizotinib, is characterized in that, by the formula 5b compound in formula 5a compound and non-deuterium generation or by the non-deuterium formula in generation
5acompound and formula
5bcompound first is dissolved in N, dinethylformamide, diethylamide, dioxane or triethylamine, add afterwards sodium carbonate, salt of wormwood, Potassium ethanoate or triethylamine, under nitrogen protection, add successively palladium, triphenyl phosphorus, be warming up to 60-150 ℃ of heated and stirred 2-24h, be cooled to room temperature, obtain deuterium after conventional aftertreatment for achirality Crizotinib derivative; Deuterium is dissolved in organic solvent for achirality Crizotinib derivative, passes into wherein hydrogen chloride gas, monitor while disappearing to derivative, concentrated, adjusting pH is alkalescence, and conventional aftertreatment afterwards obtains deuterium for the achirality Crizotinib;
Deuterium claimed in claim 1 for the achirality Crizotinib in the application aspect preparation treatment cancer drug.
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| CN107445798B (en) * | 2016-06-01 | 2020-11-03 | 中国农业大学 | Synthetic method of alpha, alpha-dideuteroalcohol compound |
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