CN108191747A - A kind of preparation method of Abemaciclib intermediates - Google Patents
A kind of preparation method of Abemaciclib intermediates Download PDFInfo
- Publication number
- CN108191747A CN108191747A CN201810208517.8A CN201810208517A CN108191747A CN 108191747 A CN108191747 A CN 108191747A CN 201810208517 A CN201810208517 A CN 201810208517A CN 108191747 A CN108191747 A CN 108191747A
- Authority
- CN
- China
- Prior art keywords
- compound
- method described
- catalyst
- formula
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Abstract
The invention discloses a kind of preparation methods of Abemaciclib intermediates, belong to field of medicine and chemical technology.The preparation method of the present invention, the carbonyl and nitro of 5 (4 ethyl piperazidine, 1 carbonyl) 2 nitropyridines are restored by priority, so as to obtain 2 base amine of Abemaciclib intermediates 5 (4 Yi Ji Veins throats, 1 ylmethyl) pyridine, this method is raw materials used and reagent is easy to get, reaction condition is mild, it avoids using toxic, irritant and strong corrosive reagent, it is environmentally protective, it prepares simple to operation, products obtained therefrom has in high yield and high-purity, is particularly suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of Abemaciclib intermediates, belong to field of medicine and chemical technology.
Background technology
Abemaciclib, entitled [5- (4- ethyl-piperazin -1- ylmethyls)-pyridine -2- bases]-[fluoro- 4- (7- of 5- of chemistry
Fluoro- 3- isopropyls -2- methyl -3H- benzo miaows frustrate -5- bases)-pyrimidine -2-base]-amine is pressed down by the CDK4/6 that Li Lai companies develop
Preparation, for oral medication breast cancer.
CN102264725A disclose Abemaciclib and its intermediate 5- (4- ethyl-piperazin -1- ylmethyls)-pyridine -
The preparation method of 2- bases amine (Formulas I), the intermediate preparation are as follows：
In the presence of sodium triacetoxy borohydride, the bromo- pyridine -3- formaldehyde of 6- and n-ethylpiperazine are anti-in methylene chloride
1- (the bromo- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins should be obtained, then further in the item of cuprous oxide, methanol and liquefied ammonia
Compound of formula I (first method) or 1- (the bromo- pyridin-3-yl methyl of 6-) -4- ethyl-piperazins are prepared under part in 2-
(dicyclohexyl phosphino-) biphenyl, three (dibenzalacetone) two palladium, tetrahydrofuran and 1 ,-two silicon nitrogen of 1,1,3,3,3- hexamethyl
It is reacted in the presence of alkane lithium, compound of formula I (second method) is prepared using a series of subsequent processings.
According to method disclosed in above-mentioned document, in actual fabrication process, first step reaction remains big content of starting materials, and reaction is not
It easily carries out, and the bromo- pyridine -3- formaldehyde of 6- is easily reduced into alcohol by sodium triacetoxy borohydride, the reaction time is longer；Second step
The first method needs of reaction are used with the strong and readily volatilized liquefied ammonia of strong excitatory smell, corrosivity, reaction condition
Harshness, yield is relatively low, yield 54.55%.Second method agents useful for same is complicated, and the subsequent processing of reaction solution is very numerous
Trivial, yield is relatively low, and yield is not suitable with industrialized production for 55.89%.Therefore the new method of preparation of compounds of formula I is still needed to, with
Adapt to the demand of industrialized production.
Existing literature discloses Abemaciclib correlation intermediates 5- (4- ethyl-piperazin -1- ylmethyls)-pyridine -2- bases
The preparation method of amine (Formulas I), the intermediate preparation are as follows：
Using methanol as solvent, temperature 50 C, in Pd/c and H2In the presence of, formula III restores to obtain formula IV by nitro.Then
Further in the presence of solvents tetrahydrofurane and reducing agent lithium aluminium hydride reduction, carbonyl reduction is obtained into formula I.
According to method disclosed in above-mentioned document, the first step is reacted in actual fabrication process, often has the reduction incomplete existing
As, and the appearance of by-product azanol is had, the yield of product is reduced to a certain extent.Second step post processing needs to add in hydrogen-oxygen
Change sodium solution, wastewater treatment is more difficult and purifying products need to use column chromatography, and purification process is not suitable for large-batch industrial life
Production.Therefore still need to prepare the new method of type I compound, to adapt to the demand of industrialized production.
Invention content
The present invention provides a kind of preparation method of type I compound, includes the following steps：
(1) in the presence of reducing agent and catalyst I, III compound of formula carries out reaction II chemical combination of formula in solvent I
Object；
(2) in the presence of catalyst II and hydrogen source, II compound of formula carries out reaction in solvent II and prepares type I compound.
In one embodiment of the invention, reducing agent described in step (1) is Me2SiClH、Et3SiH, poly- methyl hydrogen
Siloxanes (PMHS), (CH3O)2CH3SiH、PhSiH3Or ((CH3)3SiO)2CH3SiH。
In one embodiment of the invention, reducing agent described in step (1) is Me2SiClH。
In one embodiment of the invention, it is Ga (OTf) that I agent is catalyzed described in step (1)3。
In one embodiment of the invention, III compound of step (1) Chinese style：Reducing agent：Catalyst I molar ratios are 1：
0.001-100:0.001-100。
In one embodiment of the invention, III compound of step (1) Chinese style：Reducing agent：Catalyst I molar ratios are 1:
0.01-0.1：1-10.
In one embodiment of the invention, III compound of step (1) Chinese style：Reducing agent：Catalyst I molar ratios are 1:
0.05：2.5.
In one embodiment of the invention, solvent I described in step (1) is water, methanol, ethyl alcohol, isopropanol, positive fourth
Alcohol, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ether, ethyl acetate, benzene,toluene,xylene, DMF or DMSO one
Kind is several.
In one embodiment of the invention, solvent I described in step (1) is one kind of dichloromethane or chloroform
Or two kinds.
In one embodiment of the invention, solvent I described in step (1) is dichloromethane.
In one embodiment of the invention, step (1) can be heated or be carried out under room temperature.
In one embodiment of the invention, catalyst II described in step (2) is Pd (OH)2/C、Pd/C、PdCl2、
Pd(OAc)2、Pd(OH)2Or Raney Ni.
In one embodiment of the invention, catalyst described in step (2) is RaneyNi.
In one embodiment of the invention, hydrogen source described in step (2) is H2、HCOOH、HCOONH4, hydrazine hydrate or
Cyclohexene.
In one embodiment of the invention, hydrogen source described in step (2) is hydrazine hydrate.
In one embodiment of the invention, solvent II described in step (2) for methanol, ethyl alcohol, propyl alcohol, isopropanol,
N-butanol, isobutanol, the tert-butyl alcohol, Isosorbide-5-Nitrae-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone,
Hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, DMF, DMAC or
The one or more of DMSO.
In one embodiment of the invention, one or two of the solvent II described in step (2) for methanol or ethyl alcohol.
In one embodiment of the invention, solvent II described in step (2) is methanol.
In one embodiment of the invention, the mass ratio of II compound of step (2) Chinese style and catalyst II is 1:
0.001-100。
In one embodiment of the invention, the mass ratio of II compound of step (2) Chinese style and catalyst II is 1：
0.01-1。
In one embodiment of the invention, the mass ratio of II compound of step (2) Chinese style and catalyst II is 1:
0.0125。
In one embodiment of the invention, step (2) can carry out under heating conditions.
In one embodiment of the invention, step (2) is carried out under the conditions of being heated to 70 DEG C.
In one embodiment of the invention, step (2) is carried out under normal pressure or pressurized conditions.
In one embodiment of the invention, to the abstraction purification step of type I compound that is obtained in step (2) such as
Under：
Water is added in I reaction solutions；II is extracted with organic solvent unmixing with water；III is purified.
In one embodiment of the invention, the organic solvent is ethyl acetate, butyl acetate, dichloromethane, three
Chloromethanes or ether.
In one embodiment of the invention, the organic solvent is dichloromethane.
In one embodiment of the invention, the purifying is purified for crystallization purifying or column chromatography.
In one embodiment of the invention, the purifying is purified for column chromatography, wherein column chromatography purifying stream used
Dynamic is mutually dichloromethane and the mixed solvent of methanol.
Beneficial effects of the present invention：
(1) yield is high, and first step yield is up to more than 90%, and second step yield is up to 85%；
(2) method is simple, used reagent safety, cheaply, suitable for industrial mass production.Particularly the first step is anti-
Mild condition is answered, can be reacted at room temperature, without low temperature or high temperature, condition of high voltage；
(3) catalyst Ga (OTf)3It can at least recycle four times, catalytic activity still keeps fine (conversion ratio
99%).
Description of the drawings
Fig. 1：Type I compound HPLC spectrograms
Specific embodiment
For the present invention by following embodiment, they are only embodiment, are not intended to limit the present invention, every to be based on institute of the present invention
The technology of realization, all belongs to the scope of the present invention.
HPLC assay methods：Sample size 5ul, methanol and 0.2% ammonium acetate solution be mobile phase, volume ratio 60:40,
2998PDA detectors, Detection wavelength 270nm, flow velocity 0.5ml/min, 25 DEG C of column temperature, pillar C18(4.6x250mm, 5 μm),
XBridgeTM。
Formula compound yield calculation formula：After product drying, yield=actual production/theoretical yield * 100%
1 reducing agent of embodiment is to preparing 1- ethyls -4- ((6- nitro-pyridine -3- bases) methyl) piperazine (II compound of formula)
Rate influence
The formula III (0.53g, 2mmol) being dissolved in related solvents (4mL) is added to containing Ga (OTf)3(52mg,
In reaction vessel 5mol%), excessive reductant then is added in mixed solution again, associated process conditions are as shown in table 1.Room temperature
Reaction was completed by lower reaction 2h, and reaction solution is filtered and uses CH2Cl2(2X5mL) washs filter cake.The filtrate decompression of merging is concentrated.
Obtained product passes through silicagel column purified by flash chromatography (CH2Cl2:CH3OH=50:1 is used as mobile phase).
1 process conditions of table are to preparing 1- ethyls -4- ((6- nitro-pyridine -3- bases) methyl) piperazine (II compound of formula)
The influence of rate
Note：Related reagent molar ratio is n (III compound of formula) in table：N (organosilan)：n(Ga(OTf)3)=1:3:
0.05
As shown in Table 1, Me2SiClH is preferably reducing agent, CH2Cl2It is preferably reaction dissolvent, yield is just high at room temperature
Up to more than 90%.
2 catalyst Ga (OTf) of table3Dosage is to preparing 1- ethyls -4- ((6- nitro-pyridine -3- bases) methyl) piperazine (formula II
Compound) yield influence
Note：Solvent is CH in being tested in table2Cl2, reaction temperature is room temperature n (III compound of formula)：n(Me2SiClH)=1:3
As shown in Table 2, catalyst Ga (OTf)3Preferably dosage is the 5mol% of III compound of starting materials of formulae, as catalyst Ga
(OTf)3In the absence of, even if reaction 12h does not have target product generation, illustrate Ga (OTf)3It is necessary in this reaction.Increase
Catalyst Ga (OTf)3During dosage (7mol%), only it can shorten the reaction time, but yield does not increase, to reduce production cost,
Select Ga (OTf)3Optimal dosage is 5mol%.
The preparation of 2 1- ethyls -4- of embodiment ((6- nitro-pyridine -3- bases) methyl) piperazine (II compound of formula)
It is dissolved in CH2Cl2Formula III (0.53g, 2mmol) in (4mL) is added to containing Ga (OTf)3(52mg,
In reaction vessel 5mol%), excessive Et is then added in mixed solution again3SiH(0.58g,5mmol).It is reacted at 75 DEG C
Reaction was completed by 12h, and reaction solution is filtered and uses CH2Cl2(2X5mL) washs filter cake.The filtrate decompression of merging is concentrated.It obtains
Product pass through silicagel column purified by flash chromatography (CH2Cl2:CH3OH=50:1 is used as mobile phase), yield 70-75%.
The preparation of 3 1- ethyls -4- of embodiment ((6- nitro-pyridine -3- bases) methyl) piperazine (II compound of formula)
It is dissolved in CH2Cl2Formula III (0.53g, 2mmol) in (4mL) is added to containing Ga (OTf)3(52mg,
In reaction vessel 5mol%), excessive PhSiH is then added in mixed solution again3(0.54g,5mmol).It is reacted at 60 DEG C
Reaction was completed by 12h, and reaction solution is filtered and uses CH2Cl2(2X5mL) washs filter cake.The filtrate decompression of merging is concentrated, is obtained
Product pass through silicagel column purified by flash chromatography (CH2Cl2:CH3OH=50:1 is used as mobile phase), yield 78-82%.
The preparation of 4 5- of embodiment (4- ethyl-piperazin -1- ylmethyls)-pyridine -2- bases amine (type I compound)
II compound of formula (0.4g, 1.6mmol) is dissolved in methanol (15mL), then by Raney Ni (0.005g) and water
It closes hydrazine (2mL) to be added in solution, stirs heating reflux reaction 2h after 5min.The RaneyNi being filtered to remove in reaction system, first
Alcohol (2mL) rinses filter cake.Filtrate is evaporated, column chromatography (200-300 mesh silica gel, methylene chloride-methanol, volume ratio 100: 1)
Separation obtains compound of formula I 0.3g, and 1.36mmol, yield 85%, HPLC is 98.1% (area normalization method)
1H NMR(400MHz,DMSO-d6):δ 7.75 (d, J=2.4Hz, 1H), 7.26 (dd, J=8.4,2.4Hz, lH),
6.39 (d, J=8.4Hz, 1H), 5.79 (s, 2H), 3.24 (m, 2H), 2.25-2.51 (m, 10H), 0.96 (t, J=7.2Hz,
3H)。
ESI-MS[M+H]+:221.1775。
The preparation of 5 5- of embodiment (4- ethyl-piperazin -1- ylmethyls)-pyridine -2- bases amine (type I compound)
II compound of formula (1.6g, 6.4mmol), 10%Pd/C (0.25g, containing 50% water, 0.12mmol) are added to and contain
In the reaction vessel for having methanol (60mL).Reaction temperature is 40 DEG C, and Hydrogen Vapor Pressure 40psi reacts 2h in hydrogenation reactor
Stop reaction afterwards, filter reaction solution in the filter device containing diatomite layer, methanol (10mL) rinses filter cake, vacuum rotary steam
Filtrate is removed, obtains type I compound, yield 85-90%.
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not limited to the present invention, any to be familiar with this skill
The people of art without departing from the spirit and scope of the present invention, can do various change and modification, therefore the protection model of the present invention
Enclosing be subject to what claims were defined.
Claims (10)
1. a kind of preparation method of Abemaciclib intermediates, which is characterized in that described method includes following steps：
(1) in the presence of reducing agent and catalyst I, III compound of formula carries out reaction II compound of formula in solvent I；
(2) in the presence of catalyst II and hydrogen source, II compound of formula carries out reaction in solvent II and prepares type I compound；
2. according to the method described in claim 1, it is characterized in that, the reducing agent of the step (1) is Me2SiClH、Et3SiH、
Polymethyl hydrogen siloxane (PMHS), (CH3O)2CH3SiH、PhSiH3Or ((CH3)3SiO)2CH3SiH。
3. according to the method described in claim 1, it is characterized in that, catalyst I described in the step (1) is Ga (OTf)3。
4. according to the method described in claim 1, it is characterized in that, III compound of the step (1) Chinese style：Reducing agent：Catalysis
Agent I molar ratios are 1：0.001-100:0.001-100.
5. according to the method described in claim 1, it is characterized in that, solvent I described in the step (1) is water, methanol, second
Alcohol, isopropanol, n-butanol, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ether, ethyl acetate, benzene, toluene, diformazan
The one or more of benzene, DMF or DMSO.
6. according to the method described in claim 1, it is characterized in that, the catalyst II in the step (2) is Pd (OH)2/C、
Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2Or Raney Ni.
7. according to the method described in claim 1, it is characterized in that, the hydrogen source in the step (2) is H2、HCOOH、
HCOONH4, hydrazine hydrate or cyclohexene.
8. according to the method described in claim 1, it is characterized in that, the solvent II in the step (2) is methanol, ethyl alcohol, third
Alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, Isosorbide-5-Nitrae-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, penta
Ketone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene,
The one or more of DMF, DMAC or DMSO.
9. according to the method described in claim 1, it is characterized in that, II compound of formula and catalyst II in the step (2)
Mass ratio be 1:0.001-100.
10. application of any the methods of claim 1-9 on treatment breast cancer medicines are prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810208517.8A CN108191747A (en) | 2018-03-14 | 2018-03-14 | A kind of preparation method of Abemaciclib intermediates |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810208517.8A CN108191747A (en) | 2018-03-14 | 2018-03-14 | A kind of preparation method of Abemaciclib intermediates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108191747A true CN108191747A (en) | 2018-06-22 |
Family
ID=62595722
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810208517.8A Pending CN108191747A (en) | 2018-03-14 | 2018-03-14 | A kind of preparation method of Abemaciclib intermediates |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108191747A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102264725A (en) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | Protein kinase inhibitors |
| CN106316935A (en) * | 2015-06-30 | 2017-01-11 | 正大天晴药业集团股份有限公司 | Preparation method of Abemaciclib intermediate |
| CN107337634A (en) * | 2017-08-28 | 2017-11-10 | 新发药业有限公司 | A kind of preparation method of Abbe Seeley midbody compound |
-
2018
- 2018-03-14 CN CN201810208517.8A patent/CN108191747A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102264725A (en) * | 2008-12-22 | 2011-11-30 | 伊莱利利公司 | Protein kinase inhibitors |
| CN106316935A (en) * | 2015-06-30 | 2017-01-11 | 正大天晴药业集团股份有限公司 | Preparation method of Abemaciclib intermediate |
| CN107337634A (en) * | 2017-08-28 | 2017-11-10 | 新发药业有限公司 | A kind of preparation method of Abbe Seeley midbody compound |
Non-Patent Citations (2)
| Title |
|---|
| MICHAEL O. FREDERICK ET AL.: "Development of a Leuckart-Wallach Reaction in Flow for the Synthesis of Abemaciclib", 《ORG. PROCESS RES. DEV.》 * |
| 谢如刚.: "《现代有机合成化学》", 31 January 2007, 上海：华东理工大学出版社 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108047107B (en) | The preparation method of diphenyl disenenide ether compound | |
| CN108947943B (en) | Method for direct catalysis of dimerization of 5-methylfurfuryl alcohol by solid phosphotungstic acid | |
| CN102863389B (en) | Method for synthesizing benzimidazole compound | |
| CN104710402B (en) | Dicyclohexyl crown ether synthesis method | |
| CN103214446A (en) | Asymmetric synthesis method of chromanones derivate | |
| CN108191747A (en) | A kind of preparation method of Abemaciclib intermediates | |
| CN111217670B (en) | Method for catalytically reducing carbonyl in compound into methylene | |
| CN103480418B (en) | Chiral catalyst in binaphthol synthesis technology | |
| CN102718662A (en) | Method for preparing cinacalcet hydrochloride | |
| CN106316935B (en) | A kind of preparation method of Abemaciclib intermediate | |
| CN106831549B (en) | A kind of method of asymmetric synthesis of Claritin carbinoxamine | |
| CN111393338A (en) | Dorphityl-d3Medicine and its preparing method | |
| CN104803835A (en) | Method for preparing benzaldehyde and its derivatives | |
| CN114133373A (en) | Method for synthesizing precursor of vilanterol intermediate | |
| CN113214256A (en) | Synthesis method of 1, 7-diazaspiro [3.5] nonane-7-tert-butyl formate | |
| CN108479769B (en) | Method for preparing Pd nano-particles | |
| CN112680497A (en) | Method for separating prostanoid drug key intermediate (1S,5R) -Corey lactone by using biological enzyme | |
| CN111302962A (en) | Rapid method for reducing nitro in aliphatic nitro compound into amino | |
| CN111718245B (en) | Method for preparing deuterated chemicals through photocatalytic decarboxylation conversion | |
| WO2023097696A1 (en) | Method for synthesizing (1r)-1-(2,2-dimethyl-4h-1,3-benzodioxin-6-yl)-2-nitroethanol | |
| CN104230785B (en) | The synthetic method of 3-((4-chlorphenyl) sulfo-) the bromo-1-hydrogen-indole of-5- | |
| Kumar et al. | Simple and efficient method for deprotection of tetrahydropyranyl ethers by using Silica supported sodium hydrogen sulphate | |
| CN111925286B (en) | Me (Me) 2 Method for synthesizing formic acid by N-C (=O) -R solvent autocatalysis | |
| CN105152884B (en) | Preparation method of 4-methoxycyclohexanon | |
| CN102718664A (en) | Preparation method of N-allyl aniline compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180622 |
|
| RJ01 | Rejection of invention patent application after publication |