CN110156751A - A kind of new method preparing Ni Lapani and its intermediate - Google Patents
A kind of new method preparing Ni Lapani and its intermediate Download PDFInfo
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- CN110156751A CN110156751A CN201910450429.3A CN201910450429A CN110156751A CN 110156751 A CN110156751 A CN 110156751A CN 201910450429 A CN201910450429 A CN 201910450429A CN 110156751 A CN110156751 A CN 110156751A
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- 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
- C07D401/02—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 two hetero rings
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Abstract
The invention discloses a kind of new methods for preparing Ni Lapani (Niraparib) and its intermediate, using 2- aminobenzamide and (S) -4- (piperidines -3- base) aniline as raw material, PARP inhibitor Ni Lapani, total recovery 81% are synthesized through oxidative dehydrogenation coupling, with paraformaldehyde addition cyclisation two-step reaction under microwave assisted.Simple synthetic method of the present invention, reaction condition is mild, and the reaction time is short, product yield high, raw material 2- aminobenzamide is cheap and easy to get, and production cost is low, a kind of efficient short-cut method is provided for synthesis 2H- indazole compound, there is potential industrial applications prospect.
Description
Technical field
The present invention relates to the manufacture new methods of Ni Lapani and its intermediate, belong to pharmaceutical chemistry manufacturing process area.
Background technique
Ni Lapani (Niraparib) is a kind of Poly ADP ribose polymerase developed by Tesaro company, the U.S.
(PARP) inhibitor is ratified to list, trade name Zejula, mainly in March, 2017 through United States Food and Drag Administration (FDA)
For the maintenance therapy of oophoroma and the treatment of breast cancer.Its chemical name is (S) -2- [4- (piperidines -3- base) phenyl] -2H-
Indazole -7- formamide, chemical structure are as follows:
The synthetic method of document report Ni Lapani mainly has:
17 days 07 month (1) 2008 year world patent (WO 2008/084261A1) disclosed (Amide substituted
Indazoles as poly (ADP-ribose) polymerase (PARP) inhibitors), with 3- methyl -2- nitrobenzene
Formic acid is raw material, through esterification, NBS/ (BzO)2Benzyl bromide, N-methylmorpholine-N- oxide (NMMO) oxidation and 4- (piperazine
Pyridine -3- base) aniline condensation, with sodium azide processing cyclization, use NH3Ni Lapani, total recovery 8.8% is prepared in ammonolysis；2017
Disclosed in 01 day 03 month year Chinese patent (CN 106467513A) (a kind of synthetic method for preparing niraparib), using activity
MnO2/65% HNO3It is aldehyde by methyl direct oxidation in esterification products, realizes cyclization with triethyl phosphite substitution sodium azide,
Use formamide ammonification instead, Ni Lapani, total recovery 11.7% is prepared in N- acetyl group-L-Leu chiral resolution method；
The Chinese patent of on May 31st, 2017 (CN 106749181A) is disclosed (a method of prepare niraparib), by by ester
Change product and DMF-DMA, NaIO4Reaction using ammonium hydrogen carbonate and methyl esters ammonolysis, and improves to prepare corresponding benzaldehyde
(S) preparation method of -4- (piperidines -3- base) aniline, total recovery 52.0%.
On 07 17th, 2008 world patent (WO 2008/084261A1) disclosed (Amide substituted
Indazoles as poly (ADP-ribose) polymerase (PARP) inhibitors), it is original with 3- methyl benzoic acid
Material passes through acetylation, sodium nitrite/concentrated hydrochloric acid ring after 3- methyl-2-amino benzoic acid is made in nitrification, esterification, catalytic hydrogenation
Change obtains 2H- indazole -7- formic acid esters, and niraparib is prepared according still further to method (3)；Or with tetrafluoro boric acid salt made from earth containing a comparatively high percentage of sodium chloride weight
Nitridation, Schiemann react to form corresponding difluoro bezene derivative, and Ni Lapani is prepared according still further to method (1).
17 days 07 month (3) 2008 years world patent (WO 2008/084261A1) disclosed (Amide substituted
Indazoles as poly (ADP-ribose) polymerase (PARP) inhibitors), with 2H- indazole -7- formic acid esters
For raw material, by with NH3Ammonolysis, with 4- bromofluoro benzene nucleophilic displacement of fluorine, with 3- pyridine boronic acid Suzuki coupling, Flower reacts and hydrogen
Change reaction and Ni Lapani is prepared.
It is (a kind of to prepare PARP inhibitor disclosed in 15 days 03 month (4) 2017 years Chinese patent (CN 106496187A)
The synthetic method of niraparib), using 2- Methyl anthranilate as raw material, through diazotising and 3- Phenylpiperidine -1- formic acid uncle
Butyl ester coupling, Re2(CO)10/ NaOAc catalytic cyclization is protected, L- (+)-tartaric acid chiral resolution system with formamide ammonolysis, de- Boc
It is standby to obtain Ni Lapani, total recovery 14.8%.
It is (a kind of to prepare anticancer drug disclosed in the Chinese patent of on May 10th, (5) 2017 (CN 106632244A)
The novel method for synthesizing of niraparib), using 3- formoxyl -2- nitrobenzene methyl as raw material, through iron powder reducing at amine,
NaNO2/ HCl diazotising, Na2SO3It is even to be reduced into hydrazine, addition cyclisation and (S) -3- (4- bromophenyl) piperidines -1- t-butyl formate
Ni Lapani, total recovery 26.8% is prepared with formamide ammonolysis, de- Boc protection in connection.
(Regioselective N-2 disclosed in United States Patent (USP) on May 18th, (6) 2017 (US 2017/0137403A1)
Arylation of indazoles), using 1H- indazole -7- formic acid as raw material, by with tert-butylamine amidation, with (S) -3- (4-
Bromophenyl) coupling of piperidines -1- t-butyl formate, the N- tert-butyl of removing amide and the Boc protecting group of piperidines obtain Ni Lapani,
Total recovery 76.0%.
(J Am Chem Soc), 2017,139 (2): (the Selective aryne of 623-626 report
formation via Grob fragmentation from the [2+2] cycloadducts of 3-
Triflyloxyarynes), with 2- iodophenyl -1,3- bis- (trifluoromethayl sulfonic acid ester) for raw material, under the effect of Benzylphosphonium Bromide magnesium
3- trifluoro oxygroup benzyne intermediate is formed, is generated with -1,2,2- trimethoxy ethylene reaction of 1- (tertiary butyl dimethyl Si base)
[2+2] cycloaddition product breaks apart ring by Grob and forms 2,3- benzyne intermediate, with 3- { 4- [1- (tertbutyloxycarbonyl) piperazine
Pyridine -3- base] phenyl -1,2,3- oxadiazoles -3--5- alcohol occur [3+2] cycloaddition reaction obtain 2,2- dimethoxy -2- { 2-
{ 4- [1- (tertbutyloxycarbonyl) piperidines -3- base] phenyl } -2H- indazole -7- base } methyl acetate, finally by deprotection and ammonolysis
Reaction synthesis obtains racemic Ni Lapani, total recovery 14.2%.
In the above method, method (1)~(3) synthetic route is long, (S) -3- (4- the aminophenyl)-tertiary fourth of piperidines -1- formic acid
The utilization rate of ester is low, and the sodium azide used when constructing indazole ring is very dangerous.Method (4), (5) synthetic route are long, and reaction is total
Yield is low, and diazotising and reduction reaction generate a large amount of waste water and waste residue, unfriendly to environment, is unfavorable for industrialized production.Side
Method (6) synthetic route is short, and overall yield of reaction is higher, but raw material sources are not easy.Method (7) synthetic route is novel, but raw material sources
It is not easy, a large amount of isomers 2H- indazole -4- methyl acetate can be generated in [3+2] cycloaddition reaction, leads to overall yield of reaction not
Height is not suitable for industrialized production.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new method for preparing Ni Lapani and its intermediate, the preparations
Method using 2- aminobenzamide and (S) -4- (piperidines -3- base) aniline as raw material, under microwave assisted through oxidative dehydrogenation coupling and
Paraformaldehyde addition is cyclized two-step reaction and synthesizes PARP inhibitor Ni Lapani, and total recovery is up to 81%.The synthetic method and document side
Method is compared, and simple synthetic method used, raw material 2- aminobenzamide is cheap and easy to get, and overall yield of reaction is high, is reduced and is produced into
This, and reaction condition is mild, and the reaction time is short, has potential industrial applications prospect.
The invention is realized by the following technical scheme:
Prepare the new method of Ni Lapani and its intermediate, including the following steps:
(1) in the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, the 2- aminobenzamide of 10 mmol of addition, 10
(S) -4- (piperidines -3- base) aniline of~20 mmol, the oxidant of 20~30 mmol, the catalyst of 0.5~2 mmol, 1~3
The ligand of mmol, the solvent of 20~40 mL heat 30~60 DEG C of reaction 5 min~18 h.Reaction solution is cooled to room temperature, is taken out
Filter, filtrate decompression concentration, residue obtain intermediate (S)-with silica gel chromatography (eluent: petrol ether/ethyl acetate)
2- { [4- (piperidines -3- base) phenyl] azo group } benzamide；
(2) in the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- of 5 mmol is added
Base) phenyl] azo group] benzamide, the paraformaldehyde of 10~20 mmol, the catalyst of 0.25~1.5 mmol, 0.5~1
The solvent of the additive of mmol and 20~40 mL heats 60~100 DEG C of reaction 10 min~20 h.Reaction solution is cooled to room
Temperature filters, and solvent is distilled off in filtrate decompression, and residue ethyl alcohol recrystallization obtains Ni Lapani.
In invention, oxidant described in step (1) is hydrogen peroxide or tert-butyl hydroperoxide (TBHP) or carbonic acid
Silver or iodobenzene diacetate, preferably TBHP.The catalyst is stannous chloride or cuprous bromide or copper bromide, preferably
Cuprous bromide.The ligand is pyridine or 8-hydroxyquinoline or 1,10- ferrosin, preferably pyridine.The solvent is
1,2- dichloroethanes (DCE) or tetrahydrofuran (THF) or toluene, preferably toluene.Heating method used be conventional heating or
Microwave heating, since the microwave heating reaction time is short, obtained reaction solution purity is high, side reaction is few, high income, it is advantageous to for
Microwave heating；10~20 min of microwave heating reaction can be complete.
Catalyst described in step (2) is dichloro (p -Methylisopropylbenzene base) ruthenium (II) dimer ([Ru (p-
cymene)Cl2]2) or acetylacetone cobalt (III) (Co (acac)3) or ([Ru (p-cymene) Cl2]2)/(Co(acac)3), it is excellent
It is selected as ([Ru (p-cymene) Cl2]2)/(Co(acac)3).The additive is water or acetic acid or sodium acetate or di(2-ethylhexyl)phosphate
Hydrogen sodium, preferably acetic acid.The solvent be toluene, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) or 1,
4- dioxane, preferably Isosorbide-5-Nitrae-dioxane.Heating method used is conventional heating or microwave heating, due to microwave heating
Reaction time is short, and obtained reaction solution purity is high, side reaction is few, high income, and it is advantageous to be microwave heating；Microwave heating 10~
30 min reaction can be complete.
Chemical equation of the invention is as follows:
In oxidative dehydrogenation coupling reaction of the invention, in the presence of catalyst CuBr/ pyridine, Ag is used2CO3、PhI(OAc)2, mistake
Hydrogen oxide, TBHP, which make oxidant, can realize that the oxidative dehydrogenation coupling reaction of two kinds of arylamine synthesizes to obtain asymmetric fragrant azo
Compound, the product yield highest that wherein TBHP is obtained as oxidant.It tests in various Cu salt catalysts used, CuBr's urges
It is best to change performance.Microwave heating can promote the oxidative dehydrogenation coupling reaction of arylamine, need to only react 10~20 min, asymmetric even
Nitrogen product yield is up to 87%, and conventional heating needs to react 18 h, and asymmetric azo product yield is 74%.Ligand urges CuBr
It is very big to change activity influence, pyridine enables CuBr to be more effectively catalyzed the oxidative dehydrogenation coupling reaction of two kinds of arylamine as ligand, with
Good yield obtains asymmetric azo product.When the dosage deficiency of oxidant, oxidative dehydrogenation coupling reaction cannot be preferably complete
At asymmetric azo product yield is very low；When the dosage of oxidant is equal with the total amount of two kinds of arylamine, asymmetric azo product
Yield highest；The dosage of oxidant is excessive, will lead to azo-compound and is further oxided, and makes under asymmetric azo product yield
Drop.With the increase of CuBr dosage, asymmetric azo product yield is gradually increased.The dosage of pyridine is decreased or increased, it is asymmetric
Azo product yield reduces.It attempts to make solvent with ethyl alcohol, tetrahydrofuran, but asymmetric azo product yield is lower.(S) -4- (piperazine
Pyridine -3- base) aniline is excessive, and asymmetric azo product yield is lower；2- aminobenzamide is excessive, asymmetric azo product yield
Increase unobvious.With the raising of reaction temperature, asymmetric azo product yield is gradually increased, and reaction temperature is excessively high, asymmetric
Azo product yield is declined.Microwave irradiation time is too short, and asymmetric azo product yield is lower；Microwave irradiation time is too
Long, the by-product of generation increases, and reduces asymmetric azo product yield.
In addition cyclization of the invention, [Ru (p-cymene) Cl is individually used2]2Or Co (acac)3Make catalyst, it is right
Though the addition cyclization of azo-compound and paraformaldehyde has certain catalytic activity, target product yield is lower.[Ru
(p-cymene)Cl2]2With Co (acac)3Be used in combination, catalytic activity significantly improves, microwave assisted lower need to react 10~
30 min, target product yield is up to 93%, and conventional heating reacts 20 h, target product yield 86%.With 1,4- dioxy six
Ring, DMF, DMSO can obtain target product as reaction medium with preferable yield.Without using additive, addition cyclization
Also it is able to achieve, but target product yield is not high；Add HOAc, NaOAc, NaH2PO4、H2O has addition cyclization certain
Facilitation, wherein best to add the reaction effect of HOAc.Increase [Ru (p-cymene) Cl in catalyst2]2Dosage, mesh
Mark product yield is without substantially changeing；Increase Co (acac)3Dosage, the yield of target product reduces.With paraformaldehyde dosage
Increase, target product yield significantly improves, after it is 2~3 times of azo-compound that paraformaldehyde dosage, which increases, target product
Yield is without obviously increasing.Reaction temperature is improved, the progress of addition cyclization is conducive to.Reaction time is short, addition cyclization
It not can be carried out completely, target product yield is lower；Extend the reaction time, target product yield is without significant change.
The present invention is compared with literature method, simple synthetic method, and overall yield of reaction is high, raw materials used 2- aminobenzamide
It is cheap and easy to get, production cost is reduced, reaction condition is mild, and the reaction time is short.The present invention provides for synthesis 2H- indazole compound
A kind of efficient short-cut method has potential industrial applications prospect.
Specific embodiment
Embodiment 1: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine
(0.24 g, 3 mmol), iodobenzene diacetate (6.44 g, 20 mmol), toluene (20 mL), the lower 50 DEG C of reactions 15 of microwave radiation
min.Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum
Ether/ethyl acetate=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (2.12
g, 69%)。
Embodiment 2: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine
(0.24 g, 3 mmol), silver carbonate (5.51 g, 20 mmol), toluene (20 mL), the lower 50 DEG C of reactions 15 of microwave radiation
min.Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum
Ether/ethyl acetate=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (1.92
g, 62%)。
Embodiment 3: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (2.72 g, 20
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), cuprous bromide (0.28 g, 2 mmol), pyridine
(0.24 g, 3 mmol), TBHP (3.86 g, 30 mmol), toluene (30 mL), 20 min of the lower 40 DEG C of reactions of microwave radiation.
Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum ether/second
Acetoacetic ester=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (2.25 g,
73%)。
Embodiment 4: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine
(0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL), 15 min of the lower 50 DEG C of reactions of microwave radiation.
Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum ether/second
Acetoacetic ester=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (2.68 g,
87%)。
Embodiment 5: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), stannous chloride (0.10 g, 1 mmol), pyridine
(0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL), 15 min of the lower 50 DEG C of reactions of microwave radiation.
Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum ether/second
Acetoacetic ester=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (2.31 g,
75%)。
Embodiment 6: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), copper bromide (0.23 g, 1 mmol), 8- hydroxyl quinoline
Quinoline (0.44 g, 3 mmol), TBHP (2.58 g, 20 mmol), tetrahydrofuran (30 mL), the lower 60 DEG C of reactions of microwave radiation
10 min.Reaction solution is cooled to room temperature, is filtered, filtrate decompression concentration, residue silica gel chromatography (eluent: stone
Oily ether/ethyl acetate=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
(1.72 g, 56%)。
Embodiment 7: the preparation of intermediate (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, and addition 2- aminobenzamide (1.36 g, 10
Mmol), (S) -4- (piperidines -3- base) aniline (1.76 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), pyridine
(0.24 g, 3 mmol), TBHP (2.58 g, 20 mmol), toluene (20 mL), 50 DEG C of conventional heating 18 h of reaction.It will be anti-
It answers liquid to be cooled to room temperature, filters, filtrate decompression concentration, residue silica gel chromatography (eluent: petroleum ether/acetic acid second
Ester=100 ︰ 1), obtain yellow solid (S) -2- { [4- (piperidines -3- base) phenyl] azo group } benzamide (2.28 g, 74%).
The preparation of embodiment 8: Ni Lapani
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- base) phenyl] azo is added
Base] benzamide (1.04 g, 5 mmol), paraformaldehyde (0.60 g, 20 mmol), Co (acac)3 (0.18 g, 0.5
Mmol), acetic acid (0.03 g, 0.5 mmol) and Isosorbide-5-Nitrae-dioxane (30 mL), 30 min of the lower 100 DEG C of reactions of microwave radiation.
Reaction solution is cooled to room temperature, is filtered, solvent is distilled off in filtrate decompression, and residue ethyl alcohol recrystallization obtains white solid
Ni Lapani (0.83 g, 52%).
The preparation of embodiment 9: Ni Lapani
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- base) phenyl] azo is added
Base] benzamide (1.04 g, 5 mmol), paraformaldehyde (0.30 g, 10 mmol), [Ru (p-cymene) Cl2]2 (0.30
G, 0.5 mmol), Co (acac)3(0.18 g, 0.5 mmol), sodium dihydrogen phosphate (0.06 g, 0.5 mmol) and DMF
(40 mL), 30 min of the lower 90 DEG C of reactions of microwave radiation.Reaction solution is cooled to room temperature, is filtered, filtrate decompression is distilled off molten
Agent, residue ethyl alcohol recrystallization obtain white solid Ni Lapani (1.12 g, 70%).
The preparation of embodiment 10: Ni Lapani
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- base) phenyl] azo is added
Base] benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [Ru (p-cymene) Cl2]2 (0.15
G, 0.25 mmol), Co (acac)3(0.18 g, 0.5 mmol), acetic acid (0.03 g, 0.5 mmol) and Isosorbide-5-Nitrae-dioxy six
Ring (20 mL), 20 min of the lower 100 DEG C of reactions of microwave radiation.Reaction solution is cooled to room temperature, is filtered, filtrate decompression is distilled off
Solvent, residue ethyl alcohol recrystallization obtain white solid Ni Lapani (1.49 g, 93%).
The preparation of embodiment 11: Ni Lapani
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- base) phenyl] azo is added
Base] benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [Ru (p-cymene) Cl2]2 (0.30
G, 0.5 mmol), Co (acac)3(0.18 g, 0.5 mmol), water (0.01 g, 0.5 mmol) and DMSO (30 mL),
10 min of the lower 100 DEG C of reactions of microwave radiation.Reaction solution is cooled to room temperature, is filtered, solvent is distilled off in filtrate decompression, remains
Object ethyl alcohol recrystallization obtains white solid Ni Lapani (1.25 g, 78%).
The preparation of embodiment 12: Ni Lapani
In the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- base) phenyl] azo is added
Base] benzamide (1.04 g, 5 mmol), paraformaldehyde (0.45 g, 15 mmol), [Ru (p-cymene) Cl2]2 (0.15
G, 0.25 mmol), Co (acac)3(0.18 g, 0.5 mmol), acetic acid (0.03 g, 0.5 mmol) and Isosorbide-5-Nitrae-dioxy six
Ring (20 mL), 100 DEG C of conventional heating 20 h of reaction.Reaction solution is cooled to room temperature, is filtered, filtrate decompression is distilled off molten
Agent, residue ethyl alcohol recrystallization obtain white solid Ni Lapani (1.38 g, 86%).
Claims (3)
1. a kind of new method for preparing Ni Lapani and its intermediate, it is characterised in that include the following steps:
(1) in the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, it is added the 2- aminobenzamide of 10mmol, 10~
(S) -4- (piperidines -3- base) aniline of 20mmol, the oxidant of 20~30mmol, the catalyst of 0.5~2mmol, 1~3mmol
Ligand, the solvent of 20~40mL, heat 30~60 DEG C of reaction 5min~18h；Reaction solution is cooled to room temperature, is filtered, filtrate
It is concentrated under reduced pressure, residue obtains intermediate (S) -2- { [4- with silica gel chromatography (eluent: petrol ether/ethyl acetate)
(piperidines -3- base) phenyl] azo group } benzamide；
(2) in the dedicated reaction flask of microwave equipped with drying tube and condenser pipe, (S) -2- [[4- (piperidines -3- of 5mmol is added
Base) phenyl] azo group] benzamide, the paraformaldehyde of 10~20mmol, the catalyst of 0.25~1.5mmol, 0.5~
The additive of 1mmol and the solvent of 20~40mL heat 60~100 DEG C of reaction 10min~20h；Reaction solution is cooled to room temperature,
It filters, solvent is distilled off in filtrate decompression, and residue ethyl alcohol recrystallization obtains Ni Lapani.
2. preparing the new method of Ni Lapani and its intermediate as described in claim 1, it is characterised in that: institute in step (1)
The oxidant stated is hydrogen peroxide or tert-butyl hydroperoxide (TBHP) or silver carbonate or iodobenzene diacetate；The catalysis
Agent is stannous chloride or cuprous bromide or copper bromide；The ligand is pyridine or 8-hydroxyquinoline or 1,10- ferrosin；
The solvent is 1,2- dichloroethanes (DCE) or tetrahydrofuran (THF) or toluene；Heating method used be conventional heating,
Or microwave heating.
3. preparing the new method of Dasatinib and its intermediate as described in claim 1, it is characterised in that: institute in step (2)
The catalyst stated is dichloro (p -Methylisopropylbenzene base) ruthenium (II) dimer ([Ru (p-cymene) Cl2]2) or acetylacetone,2,4-pentanedione
Cobalt (III) (Co (acac)3) or ([Ru (p-cymene) Cl2]2)/(Co(acac)3)；The additive be water or acetic acid,
Or sodium acetate or sodium dihydrogen phosphate；The solvent is toluene, dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF) or 1,4- dioxane；Heating method used is conventional heating or microwave heating.
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| CN201910450429.3A CN110156751B (en) | 2019-05-28 | 2019-05-28 | Novel method for preparing nilapanib and intermediate thereof |
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| CN201910450429.3A CN110156751B (en) | 2019-05-28 | 2019-05-28 | Novel method for preparing nilapanib and intermediate thereof |
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| CN110156751B CN110156751B (en) | 2022-01-18 |
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Cited By (3)
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| CN114524800A (en) * | 2022-01-20 | 2022-05-24 | 上海陶术生物科技有限公司 | Synthesis method of nilapanib intermediate |
| CN114920699A (en) * | 2022-05-31 | 2022-08-19 | 甘肃皓天化学科技有限公司 | Method for preparing 6-chloro-2-methyl-2H-indazole-5-amine |
| CN115626891A (en) * | 2022-10-20 | 2023-01-20 | 四川轻化工大学 | Synthesis method of nilapanib key intermediate |
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| CN114920699B (en) * | 2022-05-31 | 2024-03-19 | 甘肃皓天科技股份有限公司 | Method for preparing 6-chloro-2-methyl-2H-indazol-5-amine |
| CN115626891A (en) * | 2022-10-20 | 2023-01-20 | 四川轻化工大学 | Synthesis method of nilapanib key intermediate |
| CN115626891B (en) * | 2022-10-20 | 2024-01-26 | 四川轻化工大学 | Synthesis method of nilaparib key intermediate |
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