CN103864691A - Method for preparing compound ABT-869 - Google Patents
Method for preparing compound ABT-869 Download PDFInfo
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- CN103864691A CN103864691A CN201410121685.5A CN201410121685A CN103864691A CN 103864691 A CN103864691 A CN 103864691A CN 201410121685 A CN201410121685 A CN 201410121685A CN 103864691 A CN103864691 A CN 103864691A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The invention discloses a process for synthesizing a compound ABT-869, and belongs to the field of synthesis of an organic compound. The method comprises the following steps: taking m-fluoroaniline as a raw material; conveniently preparing commercially available important intermediate with high price, namely 2-fluorine-6-iodine cyanobenzene with low cost; obtaining the compound ABT-869 by cyclization reaction and Suzuki coupled reaction. The method is short in reaction time, simple and convenient to operate, and applicable to industrial production, side reaction is reduced, the total yield of the reaction is significantly improved, and the total yield can be up to over 42.3%.
Description
Technical field
The present invention relates to the synthetic of organic compound, relate in particular to the synthesis technique of compd A BT-869.
Background technology
ABT-869 (Linifanib) is a kind of antitumor candidate's new drug for tumor tissues vasculogenesis link.It is a kind of many target spots receptor tyrosine kinase (RTK) inhibitor of novel structure, chemistry N-[4-(3-amino-1 h-indazole-4-yl) phenyl by name]-N'-(the fluoro-5-aminomethyl phenyl of 2-) urea.It can suppress and the closely-related multiple receptor tyrosine kinase of angiogenesis in the horizontal specificity of nmole, comprise vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) family's Tyrosylprotein kinase (TK) activity, be a kind of many target spots, anti-tumor drugs targeting, it is to have one of candidate compound of DEVELOPMENT PROSPECT most in a series of RTK inhibitor of studying at present.Preclinical study result shows, ABT-869 can suppress KDR phosphorylation completely in lung tissue, also can effectively suppress oedema reaction.Its anti-tumor activity is remarkable, all shows good pharmacokinetic property in different animals, and ABT-869 is in third stage conceptual phase at present.
Few about preparation method's bibliographical information of ABT-869, mainly contain following several:
1) take the fluoro-6-iodobenzene of 2-formonitrile HCN as starting raw material, obtain target compound ABT-869 through cyclization, Suzuki coupling, condensation three-step reaction, although this method route is shorter, but the fluoro-6-iodobenzene of raw materials used 2-formonitrile HCN price is relatively costly, in the time of preparation 4-(4-aminophenyl)-1H-indazole-3-base amine, yield is only 60%, and need to pass through column chromatography separating purification, be difficult to suitability for industrialized production.
2) be that starting raw material obtains intermediate 3-amino-4-iodine indazole through serial reaction with 2,6-dichlorobenzonitrile; Obtain another intermediate 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-[4-(4 with the fluoro-2-isocyanic ester-4-methylbenzene of 1-and 4-amino-benzene boric acid pinacol ester through condensation reaction, 4,5,5-tetramethyl--1,3,2-dioxane Boroethane-2-yl) phenyl] urea, two intermediates occur again Suzuki linked reaction obtain target compound (
1), although this technique is relatively simple, exist equally agents useful for same relatively costly, Suzuki linked reaction yield is lower, the drawback that comprehensive cost is higher, this technique has also been used industrial production to be difficult to the microwave reaction of realizing simultaneously.
3) with 2,6-difluorobenzonitrile (2) for starting raw material, be substituted, diazotization, ring-closure reaction, Suzuki linked reaction makes target compound ABT-869.Although used common heating device to replace microwave reaction device, simplified experimental implementation, reaction times that need to be longer, also still relatively low (39.4%) of yield in committed step Suzuki linked reaction.
Along with carrying out smoothly of ABT-869 clinical trial, development of new synthesis technique efficient, that be applicable to the ABT-869 of suitability for industrialized production has significant practical value.
Summary of the invention
The object of the invention is to provide a kind of highly effective economy, with short production cycle, and yield is higher, is easy to the preparation method of the ABT-869 of suitability for industrialized production.。
In order to realize the object of the invention, the technical solution used in the present invention is as follows:
Particularly, the synthesis technique of ABT-869 of the present invention is realized by following steps:
(a) prepare 3-fluorine iodobenzene (
3)
M-fluoroaniline is joined in the there-necked flask that fills solvent, then add H
2sO
4solution drips NaNO in cryosel is bathed
2the aqueous solution, be stirred to after system clarification, drip the KI aqueous solution, dropwise the rear room temperature that naturally rises to, Sulfothiorine saturated solution is joined in system and stirred, then use organic solvent extraction, merge organic phase, with saturated aqueous common salt and pure water washing, dry rear concentrating obtains oily matter compound successively
3.Without purifying, be directly used in the next step.Described solvent is water or the alcohols that is less than four carbon, and extraction solvent is the one in ethyl acetate, sherwood oil, chloroform, methylene dichloride.
(b) prepare 2-Fluoro-6-iodobenzoic acid (
4)
3-fluorine iodobenzene (
3) under protection of inert gas, add in the reactor that fills organic solvent, temperature control, in-75 ~-80 ℃, slowly drips alkali lye.At this temperature, stir, slowly pass into or add carbon source to system, in the time that system has solid to generate, stop ventilation.Then in system, add water termination reaction.Decompression steams after solvent, adjusts system pH=3-4 with hydrochloric acid, produces white dope.Leave standstill, discard the upper strata stillness of night, lower floor obtains compound after vacuum-drying
4.can be directly used in next step reaction.In this step reaction, alkali lye used is lithium alkylide, Lithamide class alkali, and preferably lithium diisopropylamine, carbon source used is the one in carbonic acid gas or methylcarbonate.Described organic solvent is tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile.
(c) prepare the fluoro-6-iodobenzene of 2-methane amide (
5)
By 2-Fluoro-6-iodobenzoic acid organic solvent dissolution, add again strong aqua after then adding dehydrating agent and catalyzer to stir, stirring reaction under room temperature, thin layer is followed the tracks of to detect to reaction and is finished.Decompression steams solvent, and with organic solvent extraction, organic phase with saturated sodium-chloride and pure water washing, merges organic phase successively, dry, is concentrated into dryly, obtains white solid compound
5.In this step reaction, organic solvent used is tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Dehydrating agent used is carbonyl dimidazoles (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), DIC (DIC), 4-(4,6-dimethoxy-triazine) one or more in-4-methylmorpholine muriate (DMT-MM), preferably 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), DIC (DIC); Used catalyst is 4-N, one or more in N-lutidine (DMAP), 1-hydroxy benzo triazole (HOBt), 4-pyrrolidyl pyridine (4-PPY), N-hydroxy succinic acid imines (HOSu), 1-hydroxyl-7-azo benzotriazole (HOAt), preferably 4-N, N-lutidine (DMAP) or 1-hydroxy benzo triazole (HOBt).Dehydrating agent is 1:1～1:0.01 with catalyst weight ratio, preferably 1:0.01.
(d) prepare the fluoro-6-iodobenzene of 2-formonitrile HCN (
6)
In reactor, add subsequently organic bases with the fluoro-6-iodobenzene of anhydrous organic solvent dissolving 2-methane amide, stirring at room temperature drips trifluoroacetic anhydride, stirring reaction, after reaction, add the shrend reaction of going out, remove solvent under reduced pressure, separate out white solid, filter, vacuum-drying, obtains white solid compound
6.In this step reaction, organic solvent used is tetrahydrofuran (THF), dioxane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Organic bases is the one in triethylamine, diethylamine, quadrol, diisopropylethylamine.The fluoro-6-iodobenzene of 2-methane amide: trifluoroacetic anhydride mol ratio is 1.0:1.01～2.0.
(e) prepare 1
h-3-amino-4-iodine indazole (
7)
Fluoro-2-6-iodobenzene formonitrile HCN is joined in organic solvent and dissolved, under room temperature, drip hydrazine hydrate, then pour rare gas element, temperature reaction, reaction finishes, and stops heating, after decompression steams organic solvent, adds a small amount of water, separates out solid, filter, dry, obtain light yellow solid compound
7.Solvent for use is the alcohols that is less than four carbon, preferably propyl carbinol.
(f) 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane Boroethane-2-yl) phenyl] urea (
10) synthetic
With the decentralized compound of organic solvent
8, temperature control, at 45-50 ℃, slowly drips isocyanic ester
9, stirring reaction, the reaction of high performance liquid phase tracking monitor finishes.Be cooled to solid and separated out, filtered, after being dried, obtained white solid compound
10.Organic solvent used is the one in benzene,toluene,xylene, preferably toluene.
(g) 1-[4-(3-amino-1 h-indazole-4-yl) phenyl]-3-(the fluoro-5-aminomethyl phenyl of 2-) urea (
1) synthetic
By 3-amino-4-iodine indazole (
7) with joining after organic solvent dissolution in ultrasound reactor, then add compound
10mineral alkali, catalyzer two (triphenylphosphine) palladium chloride and little water, be warming up to 60-70 ℃, stirs the lower ultrasonic response of opening, after reaction finishes, filter, filtrate organic solvent extraction, organic phase is successively with saturated aqueous common salt and pure water washing, dry rear decoloring, concentrates to obtain pale yellow powder compound
1,after acetonitrile recrystallization, obtain ABT-869 sterling, HPLC purity 99.42%.Organic solvent used is ethyl acetate, tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Mineral alkali used is the one in salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide.Hyperacoustic frequency is 5-100Hz, preferably 80Hz.
Compared with prior art, tool has the following advantages in the present invention:
1) using commercialization m-fluoroaniline cheap and easy to get is raw material, has prepared easily the fluoro-6-iodobenzene of commercially available expensive important intermediate 2-formonitrile HCN with lower cost, greatly reduces costs.
2) in the committed step of synthetic target product, use Catalyzed by Ultrasonic Wave reaction, greatly Reaction time shorten, reduces temperature of reaction, reduced side reaction, significantly improved yield and the total recovery of this step reaction, total recovery reaches more than 42.3%, easy and simple to handle, in industrial production, be easy to realize.
3) in this technique, polystep reaction solvent for use is identical, can intersect recovery, and the three wastes of generation are few; The intermediate that while technique respectively walks reaction can be directly used in the next step without purifying, and final product only needs crystallization purifying can reach the purity that is greater than 99%, without column chromatography for separation, is more suitable in industrial production.
Embodiment
Following examples illustrate technical scheme of the present invention, but protection scope of the present invention is not limited to this.
embodiment A BT-869(1) preparation
(1) prepare 3-fluorine iodobenzene (
3)
M-fluoroaniline (8.0 g, 71.8 mmol) is joined in the 250 mL there-necked flasks that fill 150 mL distilled water, then add the H of 6M
2sO
4solution (24 mL, 144 mmol) drips NaNO at temperature control 0-2 ℃ in cryosel is bathed
2(5.2 g, the 74.4 mmol) aqueous solution (25 mL), are stirred to after system clarification, drip KI(23.4 g, 141.6 mmol) aqueous solution (30 mL), dropwise the rear room temperature that naturally rises to, stirring is spent the night.Join 50 mL Sulfothiorine saturated solutions in system, to stir after 30 minutes with ethyl acetate (100 mL × 2) extraction next day, merges organic phase, by saturated aqueous common salt (30mL) washing, anhydrous Na
2sO
4the concentrated oily matter compound that obtains after dry
3(14.7 g, yield 92%).This compound, without being further purified, is directly used in next step reaction.Experimental data is as follows:
1H?NMR(400?Hz,?CDCl
3)?
δ:?6.98-7.03?(m,?2H)，7.37-7.43?(m,?1H)，7.42-7.48?(m,?1H);?HR-MS?(ESI)?calcd?for?C
6H
5FI?[M+H]
+?223.0089,?found?223.0091.
(2) prepare 2-Fluoro-6-iodobenzoic acid (
4)
In 250mL four-hole boiling flask, add 3-fluorine iodobenzene (
3) (18.9 g, 85.0 mmol), N
2under protection, liquid nitrogen ethanolic soln is cooled to-78 ℃, slowly drips the THF solution (51 mL, 102.0 mmol) of 2.0 M LDA.At this temperature, stir after 30min, by CO
2gas slowly passes in system, in the time that muddy state appears in system, stops.Naturally rise to room temperature and stir again 2 h, then in system, add 10 mL shrends to go out.Decompression steams after most THF, adds 200 ml water, and adjusting pH with the hydrochloric acid of 2N is 3.0, stirs after 10min, produces white dope.Leave standstill, discard the upper strata stillness of night, lower floor obtains compound after vacuum-drying
4(22.2 g, yield 93%).Being directly used in next step reacts without purifying.Experimental data is as follows:
1H?NMR?(400?Hz,?DMSO-
d 6 )?
δ:?7.69-7.75?(m,?1H),?7.16-7.22?(m,?2?H).?HR-MS?(ESI)?calcd?for?C
7H
5FIO
2?[M+H]
+?267.0163,?found?267.0166.
(3) prepare the fluoro-6-iodobenzene of 2-methane amide (
5)
By 2-Fluoro-6-iodobenzoic acid (7.0 g, 26.4mmol) join in the 100mL there-necked flask that fills 30mLTHF, after stirring and dissolving, add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (4.4g, 28.6mmol) and 4-N, N-lutidine (70mg, 0.26 mmol), continues stirring and adds the dense ammonia of 30 mL (massfraction 28%) after 10 minutes, under room temperature, stir 3 hours, thin layer is followed the tracks of and is detected to reaction end.Decompression steams THF, adds after ethyl acetate 30mL successively with saturated sodium-chloride and pure water washing, and organic phase anhydrous magnesium sulfate drying, is concentrated into dryly, obtains white solid compound
5(6.2 g, yield 89%).
Mp.?153-155℃.?
1H?NMR?(400?Hz,?DMSO-
d 6 )?
δ:?7.58-7.64?(m，1H),?7.08-7.16?(m,?2?H)，5.54?(s,?2H).?HR-MS?(ESI)?calcd?for?C
7H
5FINO?[M+H]
+?266.0315,?found?266.0318.
(4) prepare the fluoro-6-iodobenzene of 2-formonitrile HCN (
6)
Get the fluoro-6-iodobenzene of 2-methane amide (5.0 g, 18.9 mmol) and add in 100 mL there-necked flasks, add anhydrous THF (40 mL), triethylamine (3.4 mL, 24.5 mmol), stirring at room temperature, drips trifluoroacetic anhydride (2.9 mL, 20.7 mmol), after stirring at room temperature 2 h, add the 20 mL shrends reaction of going out, remove THF under reduced pressure, separate out white solid, filter, vacuum-drying, obtains white solid compound
6(4.2 g, yield 90%).Experimental data is as follows:
Mp?50-52℃,?
1H?NMR?(400?Hz,?DMSO-
d 6 )?
δ:?7.58-7.62?(m,?1H)，7.19-7.22?(m,?2?H).?HR-MS?(ESI)?calcd?for?C
7H
4FIN?[M+H]
+?248.0126,?found?248.0129.
(5) prepare 1
h-3-amino-4-iodine indazole (
7)
In 50 mL there-necked flasks, add the fluoro-6-iodobenzene of 2-formonitrile HCN (1.0 g, 4.05 mmol), dissolve with propyl carbinol (15 mL), under room temperature, drip massfraction and be 85% hydrazine hydrate (2 mL), then pour N
2, be warming up to after 105 ℃ of reaction 4h, stop heating, after steaming propyl carbinol, decompression adds 30 mL water, stir 5 min, separate out solid, filter, drying under reduced pressure, obtains light yellow solid compound
7(0.95 g, yield 91%).Experimental data is as follows:
Mp?154.0-155.0℃.?
1H?NMR?(400?Hz，DMSO-
d 6)?
δ：5.04(s,?2H),?6.91-6.95(m,?1H),?7.29(d,?
J=8.8Hz,?1H),?7.34(d,?
J=8.2?Hz,?1H),?11.78(s,?1H).?HR-MS?(ESI)?calcd?for?C
7H
7IN
3?[M+H]
+?260.0550,?found?260.0552.
(6) 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane Boroethane-2-yl) phenyl] urea (
10) synthetic
In 50mL there-necked flask, add compound
8(1.0 g, 4.5 mmol) and toluene 10 mL, temperature control, at 50 ℃, slowly drips isocyanic ester
9(0.76 g, 5.1 mmol), add rear continuation stirring reaction 3 h, and the reaction of high performance liquid phase tracking monitor finishes.Stirring drops to 0 ℃, has solid to separate out, and 20 mL toluene wash for filter cake after suction filtration obtain white solid compound after filtration cakes torrefaction
10(1.3g, yield 77%).Obtain through acetonitrile recrystallization compared with pure sample product on a small quantity.Experimental data is as follows:
Mp?201-202℃.?
1H?NMR?(400?Hz,?DMSO-
d 6 )?
δ:?1.30(s,?12H),?2.32(s,?3H)，6.74-6.81(m,?1H),?7.10-7.18(m,?1H),?7.45(d,?2H,?
J=9.0Hz),?7.66(d,?2H,?
J=9.0Hz),?8.02(d，1H,?
J=6.0Hz),?8.56(s,?1H),?9.22(s,?1H).?HR-MS?(ESI)?calcd?for?C
7H
7IN
3?[M+H]
+?371.2335,?found?371.2338.
(7) 1-[4-(3-amino-1 h-indazole-4-yl) phenyl]-3-(the fluoro-5-aminomethyl phenyl of 2-) urea (
1) synthetic
By 3-amino-4-iodine indazole
7(0.52 g, 2.0 mmol) use THF(15 mL) dissolve after join in ultrasound reactor, then add compound
10(0.80 g, 2.2 mmol), K
2cO
3(0.50 g, 4.7 mmol), catalyzer two (triphenylphosphine) palladium chloride (70 mg, 0.10 mmol),, water (3.0 mL), be warming up to 60 ℃, stir lower ultrasonic wave (frequency is 80Hz) reaction 15 min that open, reaction finishes.Filter, 20 mL that add water in filtrate, with ethyl acetate (20 mL × 2) extraction, organic phase is washed once with saturated aqueous common salt and pure water successively.Anhydrous Na
2sO
4activated carbon decolorizing after dry, concentrates to obtain pale yellow powder compound
1(0.65 g, yield 88.2%).After acetonitrile recrystallization, obtain ABT-869 sterling, HPLC purity 99.42%.Experimental data is as follows:
Mp?210-211℃.?
1H?NMR?(400?Hz，DMSO-
d 6 )?
δ:?2.27?(s,?3H),?4.34?(s,?2H),?6.77-6.84?(m,?1H),?6.88?(dd,?
J 1=6.1,?
J 2=1.7，1H),?7.12(dd,?
J 1=11.5,?
J 2=8.5Hz,?1H),?7.30-7.39?(m,?2H),?7.39-7.43(m,?2H),?7.60(d,?
J=8.5Hz,?2H),?8.01?(dd,?
J 1=7.9?
J 2=2.2Hz,?1H),?8.54?(d,?
J=2.7Hz,?1H),?9.23(s,?1H),?11.71?(s,?1?H);?
13C?NMR?(DMSO-
d 6 )?δ:?21.2,?108.1,?110.6,?114.4?(d,?
J=20.0Hz),?117.8,?118.6，120.5,?122.2?(d,?
J=7.5Hz),?126.1,?126.4?(d,?
J=10.1Hz),?129.1,?132.6,?133.0?(d,?
J=3.6Hz),?135.0,?138.9,?141.6,?147.8,?149.7,?151.6.?HR-MS?(ESI)?calcd?for?C
21H
19FN
5O?[M+H]
+?376.4069，found?376.4071.。
Claims (6)
1. compound
aBT-869synthesis technique, it is characterized in that, comprise following synthesis step:
(a) prepare 3-fluorine iodobenzene (
3)
M-fluoroaniline is joined in the there-necked flask that fills solvent, then add H
2sO
4solution drips NaNO in cryosel is bathed
2the aqueous solution, is stirred to after system clarification, drips the KI aqueous solution, dropwise the rear room temperature that naturally rises to, Sulfothiorine saturated solution is joined in system and stirred, then use organic solvent extraction, merge organic phase, successively with saturated aqueous common salt and pure water washing, the dry rear concentrated compound that obtains
3; Described solvent is water or the alcohols that is less than four carbon; Extraction solvent is the one in ethyl acetate, sherwood oil, chloroform, methylene dichloride;
(b) prepare 2-Fluoro-6-iodobenzoic acid (
4)
3-fluorine iodobenzene (
3) under protection of inert gas, add in the reactor that fills organic solvent, temperature control, in-75 ~-80 ℃, slowly drips alkali lye; At this temperature, stir, slowly pass into or add carbon source to system, in the time that system has solid to generate, stop ventilation; Then in system, add water termination reaction, decompression steams after solvent, adjusts system pH=3-4 with hydrochloric acid, leaves standstill, and discards the upper strata stillness of night, and lower floor obtains compound after vacuum-drying
4;alkali lye used is lithium alkylide, Lithamide class alkali; Carbon source used is the one in carbonic acid gas or methylcarbonate; Described organic solvent is tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile;
(c) prepare the fluoro-6-iodobenzene of 2-methane amide (
5)
By 2-Fluoro-6-iodobenzoic acid organic solvent dissolution, add again strong aqua after then adding dehydrating agent and catalyzer to stir, stirring reaction under room temperature, thin layer is followed the tracks of to detect to reaction and is finished; Decompression steams solvent, and with organic solvent extraction, organic phase with saturated sodium-chloride and pure water washing, merges organic phase successively, dry, is concentrated into dryly, obtains compound
5; Organic solvent used is tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Dehydrating agent used is one or more in carbonyl dimidazoles (CDI), dicyclohexylcarbodiimide (DCC), 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), DIC (DIC), 4-(4,6-dimethoxy-triazine)-4-methylmorpholine muriate (DMT-MM); Used catalyst is 4-N, one or more in N-lutidine (DMAP), 1-hydroxy benzo triazole (HOBt), 4-pyrrolidyl pyridine (4-PPY), N-hydroxy succinic acid imines (HOSu), 1-hydroxyl-7-azo benzotriazole (HOAt);
(d) prepare the fluoro-6-iodobenzene of 2-formonitrile HCN (
6)
In reactor, add subsequently organic bases with the fluoro-6-iodobenzene of anhydrous organic solvent dissolving 2-methane amide, stirring at room temperature drips trifluoroacetic anhydride, and stirring reaction, adds shrend to go out after reaction, remove solvent under reduced pressure, separates out solid, filters, and vacuum-drying, obtains compound
6; Organic solvent used is tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Organic bases is the one in triethylamine, diethylamine, quadrol, diisopropylethylamine;
(e) prepare 1
h-3-amino-4-iodine indazole (
7)
Fluoro-2-6-iodobenzene formonitrile HCN is joined in organic solvent and dissolved, under room temperature, drip hydrazine hydrate, then pour rare gas element, temperature reaction, reaction finishes, and stops heating, after decompression steams organic solvent, adds a small amount of water, separates out solid, filters, dry, obtains compound
7; Solvent for use is the alcohols that is less than four carbon;
(f) 1-(the fluoro-5-aminomethyl phenyl of 2-)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane Boroethane-2-yl) phenyl] urea (
10) synthetic
With the decentralized compound of organic solvent
8, temperature control, at 45-50 ℃, slowly drips isocyanic ester
9, stirring reaction, the reaction of high performance liquid phase tracking monitor finishes; Be cooled to solid and separated out, filtered, after being dried, obtained compound
10; Organic solvent used is the one in benzene,toluene,xylene;
(g) 1-[4-(3-amino-1 h-indazole-4-yl) phenyl]-3-(the fluoro-5-aminomethyl phenyl of 2-) urea (
1) synthetic
By 3-amino-4-iodine indazole (
7) with joining after organic solvent dissolution in ultrasound reactor, then add compound
10, mineral alkali, catalyzer two (triphenylphosphine) palladium chloride and little water, be warming up to 60-70 ℃, stir the lower ultrasonic response of opening, after reaction finishes, filter filtrate organic solvent extraction, organic phase is successively with saturated aqueous common salt and pure water washing, and dry rear decoloring, concentrates to obtain compound
1;organic solvent used is ethyl acetate, tetrahydrofuran (THF), dioxane, 1,3-dioxolane, 1, the one in 2-ethylene dichloride, acetonitrile, DMF, dimethyl sulfoxide (DMSO); Mineral alkali used is the one in salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide; Hyperacoustic frequency is 5-100Hz.
2. ABT-869 synthesis technique according to claim 1, is characterized in that, b) described in the preferred lithium diisopropylamine of Lithamide class alkali.
3. ABT-869 synthesis technique according to claim 1, is characterized in that, g) the middle preferred 80Hz of ultrasonic frequency.
4. ABT-869 synthesis technique according to claim 1, is characterized in that, the preferred 1-of dehydrating agent (3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI) or DIC (DIC); The preferred 4-N of catalyzer, N-lutidine (DMAP) or 1-hydroxy benzo triazole (HOBt).
5. the ABT-869 synthesis technique described in one of them according to claim 1-4, is characterized in that, dehydrating agent with catalyst weight than being 1:1～1:0.01.
6. the ABT-869 synthesis technique described in one of them according to claim 1-4, is characterized in that, the fluoro-6-iodobenzene of 2-methane amide in step (d): trifluoroacetic anhydride mol ratio is 1.0:1.01～2.0.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410121685.5A CN103864691A (en) | 2014-03-28 | 2014-03-28 | Method for preparing compound ABT-869 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410121685.5A CN103864691A (en) | 2014-03-28 | 2014-03-28 | Method for preparing compound ABT-869 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326985A (en) * | 2014-09-24 | 2015-02-04 | 安润医药科技（苏州）有限公司 | Preparation method of linifanib |
| CN104693123A (en) * | 2015-03-11 | 2015-06-10 | 西安交通大学 | 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof |
-
2014
- 2014-03-28 CN CN201410121685.5A patent/CN103864691A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| YUJIA DAI等: ""Discovery of N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-Aminoindazole-Based Orally Active Multitargeted Receptor Tyrosine Kinase Inhibitor"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 侯学会等: "多靶点受体酪氨酸激酶抑制剂 ABT-869 的有效合成方法", 《有机化学》 * |
| 刘海龙等: ""抗肿瘤药物linifanib的合成"", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104326985A (en) * | 2014-09-24 | 2015-02-04 | 安润医药科技（苏州）有限公司 | Preparation method of linifanib |
| CN104693123A (en) * | 2015-03-11 | 2015-06-10 | 西安交通大学 | 1H-indazole-3-aminobiphenyl compound as well as preparation method and application thereof |
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Application publication date: 20140618 |