CN104693184A - Synthesis method of crizotinib - Google Patents

Synthesis method of crizotinib Download PDF

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Publication number
CN104693184A
CN104693184A CN201510116996.7A CN201510116996A CN104693184A CN 104693184 A CN104693184 A CN 104693184A CN 201510116996 A CN201510116996 A CN 201510116996A CN 104693184 A CN104693184 A CN 104693184A
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compound
reaction
catalyzer
azoles
gram
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洪健
许忻
刘国斌
徐艳超
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An Run Pharmaceutical Technology (suzhou) Co Ltd
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An Run Pharmaceutical Technology (suzhou) Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention provides a synthesis method of crizotinib. The method comprises the following steps: performing chemical exchange reaction for a compound (10) to obtain an intermediate compound (11); adding a compound (6) to react to obtain a compound (12); performing deprotection reaction for the compound (12) to obtain crizotinib. The method is simple in steps, short in line, simple in after-processing, low in cost, and particularly suitable for industrial production; the reaction line is shown in the specification, wherein X is Br or I; Nu is MgX or ZnX; R1 and R2 are independently selected from Boc or H.

Description

Gram azoles is for the synthetic method of Buddhist nun
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to the synthetic method of a kind of gram of azoles for Buddhist nun.
Background technology
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine (crizotinib, 1), chemistry 3-[(1R)-1-(2 by name, the chloro-3-fluorophenyl of 6-bis-) oxyethyl group]-5-[1-(4-piperidyl)-1H-pyrazoles-4-base]-PA, it is Alk and the c-Met double inhibitor researched and developed by Pfizer, obtain U.S. FDA approval on August 26th, 2011 to go on the market in the U.S., commodity are called Xalkori, subsequently in Korea S, Japan and European Union's listing, within 2013, obtain CFDA approval in Discussion on Chinese Listed, Chinese commodity are called Sai Ruike.
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is first and carries out the medicine of targeted therapy to Nucleophosmin-anaplastic lymphoma kinase (ALK), is used for the treatment of late period or metastatic nonsmall-cell lung cancer (NSCLC) that the ALK positive is confirmed as in the detection ratified by FDA.ALK gene variation is considered to the Key driving factors that the cancers such as NSCLC occur.ALK is comparatively common in non-squamous cell carcinoma, non-smoking history or slight smoking history patient, but is also also found in smoking and Squamous Cell Carcinoma patient.(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine is the new drug of the 1st the treatment ALK specificity lung cancer that FDA ratified 6 years more, shows that NSCLC Therapeutic mode changes, is expected to for lung cancer individualized treatment is created a new situation.
Gram azoles of existing bibliographical information has following several synthetic method for Buddhist nun:
1, with 2; the chloro-3-fluoro acetophenone of 6-bis-is through the reduction of horse liver alcoholdehydrogenase and Mitsunobu reaction; obtained nitro-compound 5; bromide 7 is obtained through iron powder reducing and NBS process; then carry out Suzuki linked reaction with boric acid ester and obtain compound 9, provide gram azoles after deprotection for Buddhist nun (1).In the method reaction, biological enzyme reaction time consumption is longer, severe reaction conditions, and yield is lower.In addition, when palladium chtalyst Suzuki reacts, give electronic effect due to pyridinium bromide to the strong of bit amino, make the reactivity of bromide inadequate, the productive rate of Suzuki reaction is not high, not easily amplify production (Konig, P.D.et al, Org.Process Res.Dev., 2011,15, p1018-1026).
2, former legal system obtains compound 7; protect amino to obtain compound 10 through Boc, palladium chtalyst permutoid reaction generates boric acid ester 11, after sloughing Boc protection group; with compound 12, palladium chtalyst Suzuki linked reaction occurs and obtain compound 9, deprotection obtains gram azoles for Buddhist nun (1).The method reactions steps is grown, is had two steps all to use the reaction of precious metal palladium, and cost is higher, complex operation, not easily suitability for industrialized production (Cui, J.J.et al, WO2006021884).
Current gram of azoles mostly applies these two lines for the synthetic route of Buddhist nun, and route is longer, and reaction yield is low, the large usage quantity of precious metals palladium catalyst, and cost is higher, complex operation, and impurity is more, is unfavorable for large-scale commercial production.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides the synthetic method of a kind of gram of azoles for Buddhist nun, the method step is simple, and aftertreatment is simple, and yield is high and cost is low, is suitable for suitability for industrialized production.
The technical solution used in the present invention is:
On the one hand, the present invention's a kind of gram of azoles is for the synthetic method of Buddhist nun, and it comprises the following steps:
(1) in organic solvent, compound (10) issues biochemical permutoid reaction with Grignard reagent or zincon at 0 ~ 65 DEG C, obtain midbody compound (11), add compound (6) again, and 10 ~ 18 hours are reacted at a reflux temperature under the effect of catalyzer, obtain compound (12), wherein, Nu is MgX, ZnX, X is Br or I, and described organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (10) issues biochemical permutoid reaction with n-Butyl Lithium and zincon at-90 ~-70 DEG C, obtain midbody compound (11), add compound (6) again, and react at 20 ~ 100 DEG C under the effect of catalyzer, obtain compound (12), wherein, Nu is ZnX, X is Br or I, described organic solvent is selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran;
In organic solvent, compound (10) issues biochemical permutoid reaction at 80 ~ 100 DEG C with connection pinacol borate under the effect of catalyzer and alkali, obtain midbody compound (11), add compound (6) again, and react at 80 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (12), wherein Nu is x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
In organic solvent, compound (10) issues biochemical permutoid reaction with methoxyl group pinacol borate and Grignard reagent at-10 ~ 40 DEG C, obtain midbody compound (11), add compound (6) again, and react at 80 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (12), wherein Nu is x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene;
(2) obtain compound (12) in step (1), at 0 ~ 50 DEG C, deprotection reaction occurs, obtain gram azoles for Buddhist nun;
Reaction scheme is as follows:
Wherein X is Br or I;
Nu is mgX or ZnX;
R 1, R 2independently selected from Boc or H.
Further, in step (1), described catalyzer is Pd catalyzer or Ni catalyzer.
Further, described Pd catalyzer is selected from Pd (dppf) Cl 2, Pd (PPh 3) 4, Pd (PPh 3) Cl 2, Pd (acac) 2, PdCl 2(DPPE), Pd/C, Pd (CH 3cN) Cl 2.
Again further, described Ni catalyzer is selected from Ni (DPPP) Cl 2or NiCl 2(DPPE).
Further, in step (1), compound (10) is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate with the chemical exchange reaction alkali used of connection pinacol borate.
Further, in step (1), described zincon is zinc chloride or zinc bromide.
Again further, in step (1), described Grignard reagent is isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.
Further, in step (2), the deprotecting regent used of described deprotection reaction is the organic solution of hydrogenchloride or trifluoroacetic acid, the preferred dioxane solution of hydrogenchloride or the dichloromethane solution of trifluoroacetic acid.
Provided by the present invention gram of azoles can directly be bought by commercial sources for the raw material used in the synthetic method of Buddhist nun, also can be obtained by the conventional chemical processes preparation of this area, such as, present invention also offers the preparation method of compound (10) and compound (6).
Compared with prior art, the present invention has the following advantages: the invention provides the synthetic method of a kind of gram of azoles for Buddhist nun, the method overcome deficiency of the prior art, solve the low problem of the long yield of reactions steps in prior art by (one-pot) method for the treatment of different things alike.The method process controllability of the present invention is strong, and step is simple, and route is short, and does not need loaded down with trivial details last handling process, and thus yield is high.In addition, in the method, the consumption of precious metal (such as) palladium catalyst is less, cost is low, product purity is high, is particularly suitable for suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
Compound 1 (10g, 48mmol) is dissolved in (100ml) in Isosorbide-5-Nitrae-dioxane,-20 DEG C of droppings (-) DIPCl (22.8g, 72mmol), keep-20 DEG C to react 2h, add water (50ml), use saturated NaHCO 3the aqueous solution regulates pH to equal 7, is extracted with ethyl acetate (30ml × 3), dry, obtains light yellow oil, i.e. compound 2 (8.1g, 80% yield) after concentrated.
1H NMR(400MHz,CDCl 3,δppm):1.65(d,J＝6.8Hz,3H)5.58(q,J＝6.9Hz,1H)6.96-7.10(m,1H)7.22-7.36(m,1H)。
Embodiment 2
In THF (20ml) solution of compound 2 (460mg, 2.2mmol), 3-hydroxyl-2-nitropyridine (350mg, 2.42mmol) and triphenylphosphine (880mg, 3.2mmol) is added successively under nitrogen protection.Stirred at ambient temperature 1 hour, then drops to 0 DEG C, and adds DIAD (0.68mL, 3.2mmol), and continue stirring reaction 12 hours, reaction solution is spin-dried for oily, crosses post and to purify to obtain white solid (677mg, 2.04mmol, productive rate 93%).
1H NMR(400MHz,CDC l3,δppm):1.85(d,J＝6.6Hz,3H)，6.10(q,J＝6.6Hz,1H),7.04-7.13(m,1H),7.21(dd,J＝8.5,1.14Hz,1H),7.30(dd,J＝9.0,4.9Hz,1H),7.35-7.38(m,1H),8.04(dd,J＝4.6,1.3Hz,1H)。
Embodiment 3
To compound 3 (30g, reduced iron powder (25.5g is added in acetic acid (200ml) solution 0.091mol), 0.455mol), after stirred at ambient temperature reacts 5 hours, remove most acetic acid, add water (200ml), extraction into ethyl acetate (3X 250ml), the saturated NaHCO of organic phase 3wash (2 × 250ml), organic phase anhydrous Na 2sO 4after dry overanxious be spin-dried for after compound 4 (24g, productive rate: 88%).
1H NMR(400MHz,DMSO-d6,δppm):1.75(d,J＝6.6Hz,3H),5.67(brs,2H),5.97-5.92(q,J＝6.6Hz,1H),6.38-6.35(dd,J＝5.0Hz,7.7Hz,1H),6.61(d,J＝7.1Hz,1H),7.47-7.42(m,2H),7.56-7.52(dd,J＝5.0Hz,7.7Hz,1H)。
Embodiment 4
At 0 DEG C, in acetonitrile (500ml) solution of compound 4 (24g, 78.6mmol), add NBS (18.8g, 104.6mmol) in batches, and stirring reaction 1 hour at this temperature.Solution is concentrated dry, and crude product is crossed post and to be purified to obtain brown solid (20g, productive rate: 68%).
1H NMR(400MHz,DMSO-d6,δppm):1.82(d,J＝6.6Hz,3H),4.82(brs,2H),6.01-5.96(q,J＝6.6Hz,1H),6.83(d,J＝1.8Hz,1H),7.10(t,J＝8.0Hz,1H),7.33-7.30(dd,J＝8.9Hz,4.8Hz,2H),7.66(dd,J＝5.0Hz,1.8Hz,1H)。
Embodiment 5
Prepare compound (6), wherein R 1=R 2=Boc.
Under nitrogen protection, add (Boc) in dry DMF (200ml) solution of compound 5 (25.66g, 67.52mmol) 2after O (42.5g, 194.7mmol) and DMAP (1.586g, 12.98mmol) reaction solution at room temperature stir 18 hours, add saturated NaHCO 3solution (600ml), extraction into ethyl acetate (3 × 500ml), organic phases washed with water (5 × 100mL), salt is washed, anhydrous Na 2sO 4filter after dry and be spin-dried for obtain white foam solid (39.2g, productive rate: 100%).
1H NMR(400MHz,DMSO-d6,δppm):1.19(s,9H),1.39(s,9H),1.75(d,3H),6.25(q,1H),7.48(t,1H),7.59(dd,1H),7.83(d,1H),8.18(d,1H)。
Embodiment 6
Prepare compound (6a), wherein R 1for H, R 2for Boc.
Under nitrogen protection, add (Boc) in dry DMF (200ml) solution of compound 5 (25.66g, 67.5mmol) 2after O (14.7g, 67.5mmol) and triethylamine (6.8g, 67.5mmol) reaction solution at room temperature stir 3 hours, add saturated NaHCO 3solution (600ml), extraction into ethyl acetate (3 × 500ml), organic phases washed with water (5 × 100mL), salt is washed, anhydrous Na 2sO 4filter after dry and be spin-dried for obtain white foam solid (25.9g, productive rate: 80%).LC-MS(ESI，m/z)：478.9(M+1)。
Embodiment 7
At zero DEG C, in anhydrous THF (700ml) solution of compound 7 (50g, 494mmol), drip Boc 2anhydrous THF (700ml) solution of O (120.4g, 552mmol).After dripping, solution is raised to rt while stirring overnight.Solution is spin-dried for and adds the dissolving of 1.4L methylene dichloride, and solution is washed, MgSO 4drying, after filtering, organic phase is spin-dried for obtain oily compound 8 (90g, productive rate: 91%).
1H NMR(400MHz,CDCl3,δppm)：1.48(s,9H),1.80-1.93(m,4H),2.92-3.13(m,2H),3.75-3.96(m,3H)。
Embodiment 8
At zero DEG C, to compound 8 (15.88g, triethylamine (11.1ml is slowly dripped in DCM (200ml) solution 78.9mmol), 78.9mmol), then methylsulfonyl chloride (6.12ml is dripped, 78.9mmol) with DMAP (96mg, 0.78mmol).Reaction solution at room temperature stirs and spends the night, and adds water (60ml), and DCM extracts (3 × 60mL), organic phase anhydrous Na 2sO 4filter after dry and be spin-dried for obtain white solid (22.0g, productive rate: 99%).
1H NMR(400MHz,CDCl3,δppm):1.46(s,9H),1.83(m,2H),1.95(m,2H),3.04(s,3H),3.31(m,2H),3.69(m,2H),4.89(m,1H)。
Embodiment 9
Synthetic compound (10), wherein X is I.
At zero DEG C, to 4-iodine pyrazoles (218g, NaH (54g is added in batches in DMF (4L) solution 1.12mol), 1.35mol, 60%in oil), stir 1 hour under keeping this temperature, then add compound 9 (345g, 1.24mol), reaction solution is raised to 100 DEG C and stirring reaction 12 hours.Reaction solution goes out with shrend, and with EA extract (3 × 1L) organic phase dry, filter and be spin-dried for after, cross post and to purify to obtain white solid (280g, productive rate: 66%).
1H NMR(400MHz,CDCl3,δppm):1.45(s,9H),1.86(m,2H),2.07(m,2H),2.86(m,2H),4.23(m,3H),7.44(s,1H),7.49(s,1H)。
Embodiment 10
Synthetic compound (10a), wherein X is Br
At zero DEG C, to 4-bromine pyrazoles (165g, NaH (54g is added in batches in DMF (4L) solution 1.12mol), 1.35mol, 60%in oil), stir 1 hour under keeping this temperature, then add compound 9 (345g, 1.24mol), reaction solution is raised to 100 DEG C and stirring reaction 12 hours.Reaction solution goes out with shrend, and with EA extract (3 × 1L) organic phase dry, filter and be spin-dried for after, cross post and to purify to obtain white solid (265g, productive rate: 72%).
1H NMR(400MHz,CDCl 3,δppm):7.46(s,1H),7.43(s,1H),4.23(m,3H),2.88(m,2H),2.10(m,2H),1.88(m,2H),1.47(s,9H)。
Embodiment 11 (connection pinacol borate)
Under nitrogen protection, by PdCl 2(dppf) (0.45g, 0.55mmol) be added to containing formula (10) compound (1.03g, 2.74mmol), pinacol borate (1.04g is joined, 4.10mmol), Potassium ethanoate (1.07g, 10.94mmol) with in the mixing solutions of methyl-sulphoxide (35ml), be warming up to 80 DEG C, react 3 hours; Reacted solution is cooled to room temperature, and by formula (6) compound (1.32g of the above-mentioned synthesis through degassed process in advance, dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, the aqueous solution (5ml) injection 6.84mmol) is added to above-mentioned being cooled in the reacted solution of room temperature, is warming up to 80 DEG C of reactions three hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12) compound (1.31g, productive rate is 64%).LC-MS(ESI,m/z):750.3(M+l)。
Embodiment 12
Under nitrogen protection, by Pd (OAc) 2(63mg, 0.28mmol) be added to containing formula (10a) compound (904mg, 2.74mmol), pinacol borate (1.04g is joined, in the mixing solutions of 4.10mmol), sodium-acetate (10.94mmol) and methyl-sulphoxide (35ml), be warming up to 115 DEG C, react 2.5 hours; Reacted solution is cooled to room temperature, add Pd/C (30mg, 0.27mmol), after degassed, by formula (6a) compound (1.1g of the above-mentioned synthesis through degassed process in advance, the aqueous solution (5ml) injection of dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, 6.84mmol) is added to above-mentioned being cooled in the reacted solution of room temperature, is warming up to 115 DEG C of reactions 2 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (1.02g, productive rate is 69%).
Embodiment 13
Under nitrogen protection, by Pd (OAc) 2(63mg, 0.28mmol) be added to containing formula (10) compound (1.03g, 2.74mmol), pinacol borate (1.04g is joined, in the mixing solutions of 4.10mmol), Lithium Acetate (10.94mmol) and methyl-sulphoxide (35ml), be warming up to 115 DEG C, react 2.5 hours; Reacted solution is cooled to room temperature, add Pd/C (30mg, 0.27mmol), after degassed, by formula (6a) compound (1.1g of the above-mentioned synthesis through degassed process in advance, the aqueous solution (5ml) injection of dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, 6.84mmol) is added to above-mentioned being cooled in the reacted solution of room temperature, is warming up to 115 DEG C of reactions 2 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (1.35g, productive rate is 65.6%).LC-MS(ESI，m/z)：750.2(M+1)。
This step catalyzer used can be selected from PdCl 2(dppf), Pd (OAc) 2, Pd/C, PdCl 2(PPh) 3, Pd (PPh 3) 4, Pd (acac) 2, Pd (DPPE) 2in one or more.Organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Alkali used can be selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate.
Embodiment 14 (methoxyl group pinacol borate)
Formula (10) (1.03g, 2.74mmol) added in methyl-sulphoxide (35ml), reaction solution is cooled to-10 DEG C, slowly drips 2molL -1the THF solution 2.1mL of i-PrMgCl (4.2mmol).Drip and finish, room temperature reaction 2h.The THF solution 2ml of slow dropping methoxyl group pinacol borate (0.48g, 3.1mmol), temperature of reaction controls below 40 DEG C.Drip and finish, room temperature reaction 12h.Add Pd (dppf) Cl 2(197mg, 0.27mmol) after degassed, by formula (the 6) (1.3g through degassed process in advance, dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, the aqueous solution (5ml) 6.84mmol) is added in above-mentioned solution, is warming up to 100 DEG C of reactions 2 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (50ml), extraction into ethyl acetate three times (50ml × 3), merge organic phase and wash with water three times (50ml × 3), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. compound (12) (1.01g, productive rate is 59%).
Embodiment 15
Formula (10a) (904mg, 2.74mmol) added in methyl-sulphoxide (35ml), reaction solution is cooled to-10 DEG C, slowly drips 2molL -1the THF solution 2.1mL of i-PrMgCl (4.2mmol).Drip and finish, room temperature reaction 2h.The THF solution 2ml of slow dropping methoxyl group pinacol borate (0.48g, 3.1mmol), temperature of reaction controls below 40 DEG C.Drip and finish, room temperature reaction 12h.Add Pd (dppf) Cl 2(197mg, 0.27mmol) after degassed, by formula (the 6a) (1.1g through degassed process in advance, dimethyl sulfoxide solution (7ml) 2.28mmol) and sodium carbonate (0.73g, the aqueous solution (5ml) 6.84mmol) is added in above-mentioned solution, is warming up to 100 DEG C of reactions 2 hours.Naturally room temperature is down to after reacting completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (50ml), extraction into ethyl acetate three times (50ml × 3), merge organic phase and wash with water three times (50ml × 3), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. compound (12a) (815mg, productive rate is 55%).
After the present embodiment Chinese style (6) or (6a) compound add, the temperature of reaction can be selected from 80-100 DEG C; Organic solvent can be selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Alkali used is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate; Grignard reagent used is isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.
Embodiment 16 (n-Butyl Lithium and zincon)
Formula (10) compound (15.08g is added in 500ml three-necked bottle, 40mmol) with ether (80ml), pass into nitrogen, be cooled to-78 DEG C, slowly hexane solution (the 20ml of instillation 2mol/L n-Butyl Lithium, 40mmol), stirring reaction 30min, then the diethyl ether solution (140ml) adding zinc bromide (9g, 40mmol), slowly rise to room temperature after insulated and stirred reaction 1h, be concentrated into dry.Add DMF (170ml), after stirring and dissolving, add formula (6) compound (23.12g, 40mmol) and tetra-triphenylphosphine palladium (0.464g, 0.4mmol), stirring at room temperature reaction 5h.After TLC display reacts completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid (formula (12) compound, 17.98g, productive rate is 60%).
Embodiment 17
Formula (10a) compound (13.2g is added in 500ml three-necked bottle, 40mmol) with ether (80ml), pass into nitrogen, be cooled to-78 DEG C, slowly hexane solution (the 20ml of instillation 2mol/L n-Butyl Lithium, 40mmol), stirring reaction 30min, then the diethyl ether solution (140ml) adding zinc bromide (9g, 40mmol), slowly rise to room temperature after insulated and stirred reaction 1h, be concentrated into dry.Add DMF (170ml), after stirring and dissolving, add formula (6a) compound (19.2g, 40mmol) and tetra-triphenylphosphine palladium (0.464g, 0.4mmol), stirring at room temperature reaction 5h.After TLC display reacts completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid (formula (12a) compound, 15.6g, productive rate is 60%).
Embodiment 18
Formula (10) compound (15.08g is added in 500ml three-necked bottle, 40mmol) with ether (80ml), pass into nitrogen, be cooled to-78 DEG C, slowly hexane solution (the 20ml of instillation 2M n-Butyl Lithium, 40mmol), stirring reaction 30min, then the diethyl ether solution (140ml) adding zinc bromide (9g, 40mmol), slowly rise to room temperature after insulated and stirred reaction 1h, be concentrated into dry.Add DMF (170ml), after stirring and dissolving, add formula (6a) compound (19.2g, 40mmol) and tetra-triphenylphosphine palladium (0.464g, 0.4mmol), stirring at room temperature reaction 5h.After TLC display reacts completely, leach insolubles, use ethyl acetate washing leaching cake, in filtrate, add water (200ml), extraction into ethyl acetate three times (200ml × 3), merge organic phase and wash with water six times (1000ml × 6), anhydrous sodium sulfate drying, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (16.4g, productive rate is 63%).
After the present embodiment Chinese style (6) or (6a) compound add, the temperature of reaction can within the scope of 20-100 DEG C, organic solvent can be selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran.
Embodiment 19 (grignard reagent)
Magnesium chips (2.2g, 0.15mo1) He in tetrahydrofuran (THF) (40m1) add formula (10) compound (1.51g, 4mmo1) heat, formula (10) compound (15.08g is dripped after initiation reaction, tetrahydrofuran (THF) (90m1) solution 40mmo1), back flow reaction 2h.Be down to 10 DEG C, add PdCl 2(PPh) 3(300mg) with formula (6) compound (23.12g, 40mmo1), add in cold water (600m1) after 10 DEG C of reaction 2h, then methylene dichloride (100ml × 3) is used to extract, use anhydrous magnesium sulfate drying organic phase, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12) compound (16.48g, productive rate is 55%).
Embodiment 20
Magnesium chips (2.2g, 0.15mo1) He in tetrahydrofuran (THF) (40m1) add formula (10) compound (1.51g, 4mmo1) heat, formula (10) compound (15.08g is dripped after initiation reaction, tetrahydrofuran (THF) (90m1) solution 40mmo1), back flow reaction 2h.Be down to 10 DEG C, add PdCl 2(PPh) 3(300mg) with formula (6a) compound (19.2g, 40mmo1), add in cold water (600m1) after 10 DEG C of reaction 2h, then methylene dichloride (100ml × 3) is used to extract, use anhydrous magnesium sulfate drying organic phase, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (14.8g, productive rate is 57%).
The Pd catalyzer of this step is selected from Pd (dppf) Cl 2, Pd (PPh 3) 4, Pd (PPh 3) Cl 2, Pd (acac) 2, PdCl 2(DPPE), Pd/C, Pd (CH 3cN) Cl 2.
Embodiment 21
Magnesium chips (2.2g, 0.15mo1) He in tetrahydrofuran (THF) (40m1) add formula (10a) compound (1.32g, 4mmo1) add dropping formula (10a) compound (13.2g after thermal booster reaction, tetrahydrofuran (THF) (90m1) solution 40mmo1), back flow reaction 2h.Be down to 40 DEG C, add Zinc Chloride Anhydrous (6.8g, 0.05mo1), equality of temperature continues reaction 1h, add nickelous chloride/DPPE catalyzer (300mg) and formula (6) compound (23.2g, 40mmo1), add in cold water (600m1) after 40 DEG C of reaction 2h, then use methylene dichloride (100ml × 3) to extract, use anhydrous magnesium sulfate drying organic phase, filter, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12) compound (18.6g, productive rate is 62%).
Embodiment 22
Formula (10) compound (1.51g, 4mmo1) heating is added in magnesium chips (2.2g, 0.15mo1) and tetrahydrofuran (THF) (40m1).Tetrahydrofuran (THF) (90m1) solution of formula (10) compound (15.08g, 40mmo1) is dripped, back flow reaction 2h after initiation reaction.Be down to 40 DEG C, add Zinc Chloride Anhydrous (6.8g, 0.05mo1), equality of temperature continues reaction 1h, add nickelous chloride/DPPE catalyzer (300mg) and formula (6a) compound (19.2g, 40mmo1), add in cold water (600m1) after 40 DEG C of reaction 2h, then methylene dichloride (100ml × 3) is used to extract, use anhydrous magnesium sulfate drying organic phase, filter, filtering and concentrating, silica column purification obtains faint yellow solid (formula (12a) compound: 15.6g, productive rate is 60%).
In the present embodiment, zincon is selected from zinc chloride or zinc bromide.Solvent can be selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran.The nickel catalyzator of this step can be selected from Ni (DPPP) Cl 2or NiCl 2(DPPE).
Embodiment 23
Compound (10) compound (15.08g, 40mmo1) is dissolved in tetrahydrofuran (THF) (100m1), heats 40 degree.Then 1.0M methylmagnesium-chloride (45mmo1) tetrahydrofuran solution is dripped.After dropwising, heating reflux reaction 2h.Be down to 40 DEG C, add Zinc Chloride Anhydrous (6.8g, 50mmo1), equality of temperature continues reaction 1h, add NiCl2 (DPPE) catalyzer (300mg) and formula (6) compound (23.2g, 40mmo1), add in cold water (600m1) after 40 DEG C of reaction 2h, then use methylene dichloride (100ml × 3) to extract, use anhydrous magnesium sulfate drying organic phase, filter, filtrate steaming removal solvent, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12) compound (18.5g, productive rate is 61.5%).
Embodiment 24
Compound (10) compound (15.08g, 40mmo1) is dissolved in tetrahydrofuran (THF) (100m1), heats 40 degree.Then 1.0M isopropylmagnesium chloride (45mmo1) tetrahydrofuran solution is dripped.After dropwising, heating reflux reaction 2h.Be down to 40 DEG C, add Zinc Chloride Anhydrous (6.8g, 50mmo1), equality of temperature continues reaction 1h.Be down to 10 DEG C, add PdCl 2(PPh) 3(300mg) with formula (6a) compound (19.2g, 40mmo1), add in cold water (600m1) after 10 DEG C of reaction 2h, then use methylene dichloride (100ml × 3) to extract, use anhydrous magnesium sulfate drying organic phase, filter, filtrate steaming removal solvent, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (15.8g, productive rate is 60.9%).
Embodiment 25
Compound (10a) compound (13.2g, 40mmo1) is dissolved in tetrahydrofuran (THF) (100m1), heats 40 degree.Then 1.0M ethylmagnesium chloride (45mmo1) tetrahydrofuran solution is dripped.After dropwising, heating reflux reaction 2h.Be down to 40 DEG C, add Zinc Chloride Anhydrous (6.8g, 50mmo1), equality of temperature continues reaction 1h.Be down to 10 DEG C, add Pd (PPh) 4(464mg) with formula (6a) compound (19.2g, 40mmo1), add in cold water (600m1) after 10 DEG C of reaction 2h, then use methylene dichloride (100ml × 3) to extract, use anhydrous magnesium sulfate drying organic phase, filter, filtrate steaming removal solvent, filtering and concentrating, silica column purification obtains faint yellow solid, i.e. formula (12a) compound (15.2g, productive rate is 58.6%).
Grignard reagent isopropylmagnesium chloride or methylmagnesium-chloride selected by this step, ethylmagnesium bromide.
Catalyzer is selected from PdCl 2(dppf), Pd (OAc) 2, Pd/C, PdCl 2(PPh) 3,pd (PPh 3) 4, the one in Pd (acac) 2, Pd (DPPE) 2 and NiCl2 (DPPE) or several in.
Embodiment 26
To compound 12 (1.1g, add in MeOH (10ml) solution 2.06mmol) that 4NHCl/dioxane (30mL) reaction solution stirring reaction 1 is little to react completely up to a board raw material, after reaction solution is concentrated, add saturated sodium bicarbonate solution, tune pH is 7 ~ 8, CH 2cl 2extraction, after organic phase drying, after solution is spin-dried for crude product to be purified to obtain white solid (820mg, productive rate: 78%, ee value: 96.4%) through column chromatography.
1H NMR(400MHz,DMSO-d6,δppm)：1.70(m,2H),1.73(d,3H),1.82(s,3H),1.88(m,2H),2.53(m,2H),2.98(m,2H),4.09(m,1H),5.57(brs,2H),6.02(q,1H),6.83(d,1H),7.37(t,1H),7.46(s,1H),7.50(dd,1H),7.68(d,1H),7.84(s,1H)。
Embodiment 27
To the CH of compound 12a (1.3g, 2.06mmol) 2cl 2(10ml) CF is added in solution 3cOOH (10mL), completely (TLC detection), add saturated sodium bicarbonate solution, tune pH is 7 ~ 8, CH to reaction solution stirring reaction 1 hour raw material reaction 2cl 2extraction, after organic phase drying, after being spin-dried for crude product, to purify to obtain white solid (742mg, productive rate: 80%) through column chromatography.
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.

Claims (8)

1. gram azoles is for a Buddhist nun's synthetic method, it is characterized in that, comprises the following steps:
(1) in organic solvent, compound (10) issues biochemical permutoid reaction with Grignard reagent or zincon at 0 ~ 65 DEG C, obtain midbody compound (11), add compound (6) again, and 10 ~ 18 hours are reacted at a reflux temperature under the effect of catalyzer, obtain compound (12), wherein, Nu is MgX or ZnX, X is Br or I, and described organic solvent is selected from one or more in ether, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran; Or
In organic solvent, compound (10) issues biochemical permutoid reaction with n-Butyl Lithium and zincon at-90 ~-70 DEG C, obtain midbody compound (11), add compound (6) again, and react at 20 ~ 100 DEG C under the effect of catalyzer, obtain compound (12), wherein, Nu is ZnX, X is Br or I, described organic solvent is selected from one or more in DMF, dioxane, methyl tertiary butyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran;
In organic solvent, compound (10) issues biochemical permutoid reaction at 80 ~ 100 DEG C with connection pinacol borate under the effect of catalyzer and alkali, obtain midbody compound (11), add compound (6) again, and react at 80 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (12), wherein Nu is x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene; Or
In organic solvent, compound (10) issues biochemical permutoid reaction with methoxyl group pinacol borate and Grignard reagent at-10 ~ 40 DEG C, obtain midbody compound (11), add compound (6) again, and react at 80 ~ 100 DEG C under the effect of alkali and catalyzer, obtain compound (12), wherein Nu is x is Br or I, and described organic solvent is selected from one or more in DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), methyl-sulphoxide, acetonitrile, methyl tertiary butyl ether and toluene;
(2) obtain compound (12) in step (1), at 0 ~ 50 DEG C, deprotection reaction occurs, obtain gram azoles for Buddhist nun;
Reaction scheme is as follows:
Wherein X is Br or I;
Nu is mgX or ZnX;
R 1, R 2independently selected from Boc or H.
2. according to claim 1 gram of azoles is for the synthetic method of Buddhist nun, and it is characterized in that: in step (1), described catalyzer is Pd catalyzer or Ni catalyzer.
3. according to claim 2 gram of azoles is for the synthetic method of Buddhist nun, it is characterized in that: described Pd catalyzer is selected from Pd (dppf) Cl 2, Pd (PPh 3) 4, Pd (PPh 3) Cl 2, Pd (acac) 2, PdCl 2(DPPE), Pd/C, Pd (CH 3cN) Cl 2.
4. according to claim 3 gram of azoles is for the synthetic method of Buddhist nun, it is characterized in that: described Ni catalyzer is selected from Ni (DPPP) Cl 2or NiCl 2(DPPE).
5. according to claim 1 gram of azoles is for the synthetic method of Buddhist nun, it is characterized in that: in step (1), compound (10) is selected from one or more in Potassium ethanoate, sodium-acetate, ammonium acetate, Lithium Acetate and cesium acetate with the chemical exchange reaction alkali used of connection pinacol borate.
6. according to claim 1 gram of azoles is for the synthetic method of Buddhist nun, and it is characterized in that: in step (1), described zincon is zinc chloride or zinc bromide.
7. according to claim 1 gram of azoles is for the synthetic method of Buddhist nun, and it is characterized in that: in step (1), described Grignard reagent is isopropylmagnesium chloride, methylmagnesium-chloride or ethylmagnesium bromide.
8. according to claim 1 gram of azoles is for the synthetic method of Buddhist nun, and it is characterized in that: in step (2), the deprotecting regent used of described deprotection reaction is the organic solution of hydrogenchloride or trifluoroacetic acid.
CN201510116996.7A 2015-03-17 2015-03-17 Synthesis method of crizotinib Pending CN104693184A (en)

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Cited By (6)

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CN105294657A (en) * 2015-10-30 2016-02-03 西华大学 Preparation method of crizotinib
CN105906656A (en) * 2016-05-17 2016-08-31 凯莱英医药集团（天津）股份有限公司 Synthetic method of crizotinib intermediate
CN106317024A (en) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 Crizotinib intermediate, preparation method and crizotinib preparation method
CN108069863A (en) * 2016-11-17 2018-05-25 武汉武药制药有限公司 A kind of method for synthesizing norepinephrine
CN108191833A (en) * 2018-01-17 2018-06-22 浙江树人学院 Gram azoles is for Buddhist nun's derivative and its preparation method and application
CN108341802A (en) * 2018-04-16 2018-07-31 浙江科聚生物医药有限公司 A kind of antitumor drug gram azoles replaces the synthetic method of Buddhist nun

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294657A (en) * 2015-10-30 2016-02-03 西华大学 Preparation method of crizotinib
CN105906656A (en) * 2016-05-17 2016-08-31 凯莱英医药集团（天津）股份有限公司 Synthetic method of crizotinib intermediate
CN105906656B (en) * 2016-05-17 2018-01-23 凯莱英医药集团（天津）股份有限公司 A kind of gram of azoles replaces the synthetic method of Buddhist nun's intermediate
CN106317024A (en) * 2016-08-19 2017-01-11 上海艾康睿医药科技有限公司 Crizotinib intermediate, preparation method and crizotinib preparation method
CN108069863A (en) * 2016-11-17 2018-05-25 武汉武药制药有限公司 A kind of method for synthesizing norepinephrine
CN108069863B (en) * 2016-11-17 2020-08-11 武汉武药制药有限公司 Method for synthesizing norepinephrine
CN108191833A (en) * 2018-01-17 2018-06-22 浙江树人学院 Gram azoles is for Buddhist nun's derivative and its preparation method and application
CN108341802A (en) * 2018-04-16 2018-07-31 浙江科聚生物医药有限公司 A kind of antitumor drug gram azoles replaces the synthetic method of Buddhist nun
CN108341802B (en) * 2018-04-16 2020-09-08 浙江科聚生物医药有限公司 Synthesis method of antineoplastic drug crizotinib

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