CN104761556B - Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method - Google Patents
Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method Download PDFInfo
- Publication number
- CN104761556B CN104761556B CN201510124650.1A CN201510124650A CN104761556B CN 104761556 B CN104761556 B CN 104761556B CN 201510124650 A CN201510124650 A CN 201510124650A CN 104761556 B CN104761556 B CN 104761556B
- Authority
- CN
- China
- Prior art keywords
- cloth
- support method
- acid
- impurity
- support
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Landscapes
- Chemical & Material Sciences (AREA)
- Physics & Mathematics (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Organic Chemistry (AREA)
- Pathology (AREA)
- Immunology (AREA)
- High Energy & Nuclear Physics (AREA)
- Electrochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the quality control method that a kind of support method replaces cloth for cloth intermediate impurities, support method for cloth impurity and its synthetic method and support method.Wherein, support method has a chemical formula in formula (I) for cloth intermediate impurities, and support method has chemical formula in formula (II) for cloth impurity.The present invention replaces cloth impurity by providing above-mentioned support method for cloth intermediate impurities and Tuo Fa, there is provided one kind monitoring optimization N methyl Ns ((3R, 4R) the base of 4 methyl piperidine 3) 7H pyrrolo-es [2,3 D] amine of pyrimidine 4 (support method replace cloth) quality standard reference material, and then be conducive to carrying out qualitative and quantitative analysis for cloth for cloth intermediate and Tuo Fa to support method.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of support method for cloth intermediate impurities, support method for cloth impurity and
Its synthetic method and support method replace the quality control method of cloth.
Background technology
On November 6th, 2012, the support method developed by Pfizer Inc. replaces cloth (tofacitinib) citrate (commodity
Name:Xeljanz) ratified to list by FDA (Food and Drug Adminstration), the medicine is used for insufficient to methotrexate for treatment response or not
It is a kind of new oral JAK inhibitor to the adult patient of severe active rheumatoid arthritis in tolerance.
At present, in the synthetic method of most of " support method replaces cloth ", support method is for cloth by N- methyl-N- ((3R, 4R) -4- methyl
Piperidines -3- bases) -7H- pyrrolo-es [2,3-D] pyrimidine -4- amine obtains for starting material and cyanoacetic acid react.Such as Chinese patent
Synthetic method proposed in CN1195755, CN101233138A and CN1729192A uses this synthetic route.Therefore N-
The direct shadow of purity of methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrrolo-es [2,3-D] pyrimidine -4- amines
Ring purity of the support method for cloth.
" N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrrolo-es [2,3-D] pyrimidine -4- amine (compounds
A) " synthesize generally by hydrogenation.For example in Chinese patent CN1729192A, CN1195755C and CN101233138A
The method for disclosing hydrogenation debenzylation.For example disclose simultaneously de- in hydrogenation debenzylation in Chinese patent CN101233138A again
The chlorine atom gone on pyrimidine ring." N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrrolo-es [2,3-D] pyrimidine -
Several synthetic routes of 4- amine (compound A) " are as follows：
In above-mentioned hydrogenation synthesis, " N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrrolo-es [2,3-D] are phonetic
In four kinds of routes of pyridine -4- amine (compound A hereinafter referred to as asks method to replace cloth) ", for compound B and compound D, contain
The preparation of chlorine compound C is easy, and yield is (up to 95%-100%) higher, typically can be the first-selected route for declaring producer.
How the quality of chlorine-containing compound C is preferably monitored, and further the support method prepared by monitoring optimization replaces cloth
Quality has become a new research and development problem of researcher.
The content of the invention
The invention aims to monitor optimization N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrroles
And the quality of [2,3-D] pyrimidine -4- amine (support method replaces cloth), there is provided a kind of support method replaces cloth impurity for cloth intermediate impurities, support method
And its synthetic method and support method replace the quality control method of cloth.
In order to optimize N- methyl-N- ((3R, 4R) -4- methyl piperidine -3- bases) -7H- pyrrolo-es [2,3-D] pyrimidine -4- amine
The quality of (support method replaces cloth), building-up process of the present inventor to support method for cloth has carried out substantial amounts of research, particularly to the back of the body
What scape technology segment was proposed is combined to " N- methyl-N- ((3R, 4R) -4- methyl piperidines -3- by feed hydrogen of chlorine-containing compound C
Base) -7H- pyrrolo-es [2,3-D] pyrimidine -4- amine (compound A) " synthetic route carried out substantial amounts of research, it is once accidental
Chance, present inventor has found to be that Material synthesis support method replaces cloth with chlorine-containing compound C (calling support method in the following text for cloth intermediate)
During, the chlorine atom on pyrimidine ring is difficult hydrogenation and sloughs, and easily forms impurity.And contain the chlorine-containing compound C of this impurity
While obtaining support method for cloth with cyanoacetic acid derivatives reaction, corresponding impurity can be also generated.If can be in the middle of these
Impurity is studied, and is beneficial to monitor and improve quality of the support method for cloth for the reference substance of cloth product as support method.
Therefore, in one aspect of the invention, there is provided a kind of support method replaces cloth intermediate impurities (N- ((3R, 4R) 4- methyl
Piperidines -3- bases)-N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -4- amine), the support method has formula for cloth intermediate impurities
(I) chemical formula in.
In the second aspect of the invention, there is provided a kind of above-mentioned support method replaces the synthetic method of cloth intermediate impurities, the conjunction
Comprised the following steps into method：Under the conditions of hydrogenation, in the presence of the first organic solvent and the first catalyst, by the support
Method is contacted for cloth intermediate with the first acid solution, and hydrogenation forms the intermediate impurities, wherein, the support method is in the middle of cloth
The chemical structural formula of body is as follows：
Preferably, above-mentioned hydrogenation condition includes：In a hydrogen atmosphere, pressure is 0.1-0.5MPa；Temperature is 60-90
Under the conditions of DEG C, 5-10h is reacted, under the conditions of preferably 70-75 DEG C, react 6-8h.
Preferably, above-mentioned first acid solution is 1 for the mol ratio of cloth intermediate with the support method:1-2:1, preferably 1.3-
1.4:1；First acid solution is inorganic acid and/or organic acid, and preferably described organic acid is glacial acetic acid, formic acid and trifluoroacetic acid
In one or more, preferably described inorganic acid be hydrochloric acid and/or sulfuric acid.
Preferably, it is defined for cloth intermediate by every Ke Tuofa, the consumption of first organic solvent is 5-10ml, preferably institute
It is one or more in methyl alcohol, ethanol, acetonitrile, ethylene glycol, acetone, propyl alcohol and isopropanol to state the first organic solvent.
Preferably, above-mentioned first catalyst is 1-8 for the mol ratio of cloth intermediate with the support method:100, preferably 3-5:
100, preferably described first catalyst is hydroxide palladium carbon, palladium carbon, one or more in platinum carbon.
A kind of support method is additionally provided for cloth impurity (3- (3R, 4R) -4- methyl -3- (methyl in the third aspect of the invention
(chloro- 7H- pyrrolo-es [2, the 3-D] pyrimidine-4-yls of 2-) amino) piperidin-1-yl) -3- OPNs), the support method has for cloth impurity
There is chemical constitution in formula (II).
A kind of synthetic method of above-mentioned support method for cloth impurity, the synthetic method are additionally provided in the fourth aspect of the invention
Comprise the following steps：It is in the presence of the second organic solvent and the second catalyst, above-mentioned support method of the invention is miscellaneous for cloth intermediate
Mixed system obtained and nucleophilic substitution with cyano-containing organic compound in matter formula (I) there is；The acid adding extraction in the mixed system
Take, then add alkali regulation pH, be stirred at room temperature, be filtrated to get support method for cloth impurity formula (II) compound.
Preferably, the condition of nucleophilic substitution is in above-mentioned synthetic method：Reaction temperature is 25-40 DEG C, reaction time
It is 8-12h；Preferably after nucleophilic substitution, room temperature is cooled to, adds acid extraction, then add weak base salt to adjust pH value to neutrality,
Stir 6-20h at room temperature, filter the support method replace cloth impurity.Preferably, the salt of 1mol/L is added in the step of acid adding is extracted
Acid extraction 1-5 times, plus it is subcarbonate, preferably NaHCO that weak base salt adjusts pH value to weak base salt described in neutral step3
And/or KHCO3。
Preferably, above-mentioned cyano-containing organic compound is 2 for the mol ratio of cloth intermediate impurities with the support method:1-6:1,
Preferably 4:1., more preferably described cyano-containing organic compound is cyan-acetic ester, cyanoacetic acid and cyanoacetic acid N- hydroxyls
One or more in succimide ester
Preferably, above-mentioned second catalyst is 0.2 for the mol ratio of cloth intermediate impurities formula (I) with the support method:1-
1.5:1, preferably 0.8:1；It is preferred that second catalyst be carbon -7- alkene (DBU) of 1,8- diazabicylos 11, triethylamine,
One or more in pyridine, oxalyl chloride and trimethyl-aceyl chloride.
Preferably, it is defined for cloth intermediate impurities formula (I) by every Ke Tuofa, the consumption 5- of second organic solvent
10ml；
It is preferred that second organic solvent is n-butanol, methyl alcohol, propane diols, 2- methyltetrahydrofurans and N- crassitudes
One or more in ketone；
A kind of quality control method of support method for cloth is additionally provided in the 5th part of the invention, the method includes：With
Above-mentioned support method replaces impurity prepared by the synthetic method of cloth impurity as standard items, and the quality to prepared support method for cloth is supervised
Control；It is preferred that also include replacing impurity prepared by the synthetic method of cloth intermediate impurities as standard items using above-mentioned support method, to prepared
Support method be monitored for the quality of cloth intermediate.
Support method according to prepared by method provided by the present invention replaces the purity of cloth impurity for cloth intermediate impurities and Tuo Fa
It is higher, may be used as reference substance and support method is compareed for cloth intermediate and Tuo Fa for cloth, cloth intermediate and support are replaced to support method
Method carries out qualitative and quantitative analysis for cloth.
Brief description of the drawings
The Figure of description for constituting the part of the application is used for providing a further understanding of the present invention, of the invention to show
Meaning property and its illustrates, for explaining the present invention, not constitute inappropriate limitation of the present invention embodiment.In the accompanying drawings：
Fig. 1 shows the mass spectrogram for cloth intermediate impurities according to support method of the present invention；
Fig. 2 shows the hydrogen nuclear magnetic resonance spectrogram for cloth intermediate impurities according to support method of the present invention；
Fig. 3 shows the carbon-13 nmr spectra figure for cloth intermediate impurities according to support method of the present invention；
Fig. 4 shows the liquid chromatogram for cloth intermediate impurities according to support method of the present invention；
Fig. 5 shows the liquid chromatogram for replacing cloth intermediate for cloth intermediate impurities and Tuo Fa according to support method of the present invention；
Fig. 6 shows the mass spectrogram for cloth impurity according to support method of the present invention；
Fig. 7 shows the carbon-13 nmr spectra figure for cloth impurity according to support method of the present invention；
Fig. 8 shows the carbon-13 nmr spectra figure for cloth impurity according to support method of the present invention；
Fig. 9 shows the liquid chromatogram for cloth impurity according to support method of the present invention；
Figure 10 shows the liquid chromatogram for replacing cloth for cloth impurity and citric acid support method according to support method of the present invention.
Specific embodiment：
Below in conjunction with specific embodiment 1-7, the present invention is described in detail, and embodiment provided by the present invention is only to use
To help understand technical scheme provided by the present invention, and protection scope of the present invention can not be limited；The present invention can be by right
It is required that the multitude of different ways for limiting and covering is implemented.
First, support method replaces the synthesis of cloth intermediate impurities
(1) embodiment 1 to 4
Embodiment 1：
The conjunction of N- ((3R, 4R) 4- methyl piperidine -3- bases)-N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -4- amine
It is as follows into method：
In the hydrogenation reaction cauldron of dry 500ml, sequentially add and replace cloth intermediate containing 21.7g (59mmol) support methods
The 110ml ethanol of (aforesaid compound C), hydrochloric acid 83ml, 4.2g (3mmol) hydroxide palladium carbon (20%) of 1mol/L, first passes through
Nitrogen displacement falls the air (at least three times) in reactor, then the nitrogen (at least three times) in reactor is displaced with hydrogen,
Under normal pressure, 70-75 DEG C of reaction, TLC monitoring reactions, 6h reactions terminate.Heat filtering removes catalyst, stands, and has solid to separate out, mistake
Filter, gained solid carries out column chromatography (SiO2, CH2Cl2：CH3OH=1:5) purify, rotation solvent evaporated obtains solid, is placed in vacuum
Dry 4h and obtain target product.
Embodiment 2：
The conjunction of N- ((3R, 4R) 4- methyl piperidine -3- bases)-N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -4- amine
It is as follows into method：
In the hydrogenation reaction cauldron of dry 500ml, sequentially add and replace cloth intermediate containing 21.7g (59mmol) support methods
The 130ml ethanol of (aforesaid compound C), hydrochloric acid 78ml, 2.5g (1.8mmol) hydroxide palladium carbon (20%) of 1mol/L, first leads to
The air (at least three times) crossed during nitrogen displacement falls reactor, then the nitrogen (at least three times) in reactor is displaced with hydrogen,
Under 0.3MPa, 70-75 DEG C of reaction, TLC monitoring reactions, 8h reactions terminate.Heat filtering removes catalyst, stands, and has solid to analyse
Go out, filter, gained solid carries out column chromatography (SiO2, CH2Cl2：CH3OH=1:5) purify, rotation solvent evaporated obtains solid, is placed in
Vacuum drying 4h obtains target product.
Embodiment 3：
The conjunction of N- ((3R, 4R) 4- methyl piperidine -3- bases)-N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -4- amine
It is as follows into method：
In the hydrogenation reaction cauldron of dry 500ml, sequentially add and replace cloth intermediate containing 21.7g (59mmol) support methods
The 175ml ethanol of (aforesaid compound C), trifluoroacetic acid 60ml, 1.27g (0.6mmol) palladium carbon (10%) of 1mol/L, first passes through
Nitrogen displacement falls the air (at least three times) in reactor, then the nitrogen (at least three times) in reactor is displaced with hydrogen,
Under 0.5MPa, 60-65 DEG C of reaction, TLC monitoring reactions, 10h reactions terminate.Heat filtering removes catalyst, stands, and has solid to analyse
Go out, filter, gained solid carries out column chromatography (SiO2, CH2Cl2：CH3OH=1:5) purify, rotation solvent evaporated obtains solid, is placed in
Vacuum drying 4h obtains target product.
Embodiment 4：N- ((3R, 4R) 4- methyl piperidine -3- bases)-N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -
The synthetic method of 4- amine：
In the hydrogenation reaction cauldron of dry 500ml, sequentially add and replace cloth intermediate containing 21.7g (59mmol) support methods
The 220ml ethanol of (aforesaid compound C), sulfuric acid 118ml, 10.2g (4.8mmol) palladium carbon (10%) of 1mol/L, first passes through nitrogen
Gas displaces the air (at least three times) in reactor, then the nitrogen (at least three times) in reactor is displaced with hydrogen, normal
Pressure, 85-90 DEG C of reaction, TLC monitoring reactions, 5h reactions terminate.Heat filtering removes catalyst, stands, and has solid to separate out, mistake
Filter, gained solid carries out column chromatography (SiO2, CH2Cl2：CH3OH=1:5) purify, rotation solvent evaporated obtains solid, is placed in vacuum
Dry 4h and obtain target product.
(2) synthesized support method replaces the detection of cloth intermediate impurities in embodiment 1
1) Mass Spectrometer Method：
As shown in figure 1, the support method synthesized by embodiment 1 replaces the ESI-MS of cloth intermediate impurities：m/z 280.3.
2) hydrogen spectrum detection：
As shown in Fig. 2 the support method synthesized by embodiment 1 replaces HNMR (400HMZ, DMSO) δ (ppm) of cloth intermediate impurities：
11.95 (s,1H, NH), 9.64,9.62 (s,1H, NH), 7.20-7.22 (d,1H, CH), 6.63 (d,1H, CH), 5.03 (d,1H,
CH), 3.59,3.57 (m,1H, CH2), 3.31,3.29 (m,1H, CH2), 3.21 (s,3H,CH3),3.11-3.17(m,1H,CH2),
2.98(m,1H,CH2), 2.51 (m,1H,CH2), 2.43 (m,1H,CH2), 1.68,1.65 (d,1H,CH2), 1.07 (s,3H,CH3)
As shown in figure 3, the support method synthesized by embodiment 1 replaces CNMR (400HMZ, DMSO) δ (ppm) of cloth intermediate impurities：
157.09,152.34,151.69,121.72,102.04,100.84,52.41,40.32,38.27,33.72,29.29,
27.89, 12.06。
From above-mentioned inspection result, product as prepared by embodiment 1 for N- ((3R, 4R) 4- methyl piperidine -3- bases) -
N- methyl-(2- chloro- 7H- pyrroles [2,3-D] pyrimidine) -4- amine, i.e., the support method to be obtained of the invention replaces cloth intermediate impurities.It is real
The corresponding data for applying a 2-4 is similar with embodiment 1, is not repeated to provide herein, it can be seen that embodiment 1-4 is institute of the present invention
The support method to be obtained replaces cloth intermediate impurities.
(3) purity testing
Measuring method：HPLC analyses will be carried out as obtained in embodiment 1-4 by solid sample, by finding out support method in the middle of cloth
Peak corresponding to body impurity, and according to its purity of calculated by peak area.
Measurement result：As shown in table 1.
Table 1
| Embodiment is numbered | Support method replaces cloth intermediate impurities purity (weight %) |
| Embodiment 1 | 99.7 |
| Embodiment 2 | 99.8 |
| Embodiment 3 | 99.3 |
| Embodiment 4 | 99.2 |
As it can be seen from table 1 having more than 99.2% for cloth intermediate impurities using the support method that the method for the present invention synthesizes
Purity, comply fully with the purity requirement of standard items, and can be used as standard items.
(4) embodiment 1 to 4 as standard items application
Liquid chromatographic detection
Detection method：Reversed-phase liquid chromatography post (bonded silica gel such as C18, C8, phenyl is the analytical column of filler) is used, is detected
Device is UV-detector, with acetonitrile and trifluoroacetic acid cushioning liquid as mobile phase, is examined according to isocratic and gradient elution program
Survey.
Test condition：Use chromatographic column：Luna5u C18, particle diameter is 5um；Column temperature：30 DEG C, flow velocity：1.0ml/min, stream
Dynamic phase：The trifluoroacetic acid water of A 0.01%, the trifluoroacetic acid acetonitrile solutions of B 0.01%
Mobile phase according to the form below gradient elution program：
Test result：As shown in Figure 4 and Figure 5.Fig. 4 shows the liquid phase color for cloth intermediate impurities according to support method of the present invention
Spectrogram；Fig. 5 shows the liquid chromatogram for replacing cloth intermediate for cloth intermediate impurities and Tuo Fa according to support method of the present invention.
As seen from Figure 5, can simultaneously detect that support method replaces cloth intermediate impurities and support by liquid phase chromatography detection method
Method replaces cloth intermediate, and both have good separating degree.Can be detected in support method in the middle of cloth by liquid phase chromatography detection method
In production procedure hold in the palm method for cloth intermediate impurities content, and other impurities content, and then be conducive to support method replace cloth
Intermediate and Tuo Fa carry out qualitative and quantitative analysis for cloth, replace the quality of cloth intermediate to support method preferably to improve.
2nd, support method replaces the synthesis of cloth impurity
(1) embodiment 5-7
Embodiment 5：(3- (3R, 4R) -4- methyl -3- (methyl (chloro- 7H- pyrrolo-es [2,3-D] pyrimidine-4-yls of 2-) ammonia
Base) piperidin-1-yl) -3- OPNs) and (support method replace cloth impurity) synthesis step it is as follows：
To 30ml n-butanols are added in 100ml round-bottomed flasks, stirring is opened, sequentially add 10g (40.8mmol) embodiment 1
Prepared support method replaces cloth intermediate impurities, 18.4g (163.2mmol) cyan-acetic esters and 5.1g (32.6mmol) DBU, plus
Hot to 40 DEG C reaction 8h.Reaction solution is cooled to room temperature, adds the aqueous hydrochloric acid solution of 1mol/L to be extracted twice, combining water layer, then
Add NaHCO3It is neutrality to adjust pH value, is stirred overnight at room temperature, is filtered, water washing filter cake, by solid acetonitrile：Water=3:1 is molten
Liquid washes and starches 2h at room temperature, filtering, and gained solid is placed in and about 7-8h is dried in 50 DEG C of vacuum drying chambers, obtains about 9g support methods and replaces cloth
Impurity.
Embodiment 6：
(3- (3R, 4R) -4- methyl -3- (methyl (chloro- 7H- pyrrolo-es [2,3-D] pyrimidine-4-yls of 2-) amino) piperidines -1-
Base) -3- OPNs) (support method replace cloth impurity) synthesis step it is as follows：
To 30ml n-butanols are added in 100ml round-bottomed flasks, stirring is opened, sequentially add 10g (40.8mmol) embodiment 1
Prepared support method replaces cloth intermediate impurities, 9.2g (81.6mmol) cyan-acetic esters and 3.2g (20.4mmol) DBU, room temperature
Lower reaction 12h.Reaction solution is cooled to room temperature, adds the aqueous hydrochloric acid solution of 1mol/L to be extracted twice, combining water layer is added
NaHCO3It is neutrality to adjust pH value, is stirred overnight at room temperature, is filtered, water washing filter cake, by solid acetonitrile：Water=3:1 solution exists
2h is washed and starched at room temperature, is filtered, gained solid is placed in and about 7-8h is dried in 50 DEG C of vacuum drying chambers, obtain about 9g support methods miscellaneous for cloth
Matter.
Embodiment 7：
(3- (3R, 4R) -4- methyl -3- (methyl (chloro- 7H- pyrrolo-es [2,3-D] pyrimidine-4-yls of 2-) amino) piperidines -1-
Base) -3- OPNs) (support method replace cloth impurity) synthesis step it is as follows：
To 30ml n-butanols are added in 100ml round-bottomed flasks, stirring is opened, sequentially add 10g (40.8mmol) embodiment
Prepared support method replaces cloth intermediate impurities, 27.6g (244.8mmol) cyan-acetic esters and 9.6g (61.2mmol) DBU, plus
Hot to 30 DEG C reaction 10h.Reaction solution is cooled to room temperature, adds the aqueous hydrochloric acid solution of 1mol/L to be extracted twice, combining water layer, then
Add NaHCO3It is neutrality to adjust pH value, is stirred overnight at room temperature, is filtered, water washing filter cake, by solid acetonitrile：Water=3:1 is molten
Liquid washes and starches 2h at room temperature, filtering, and gained solid is placed in and about 7-8h is dried in 50 DEG C of vacuum drying chambers, obtains about 9g support methods and replaces cloth
Impurity.
(2) support method replaces the detection of cloth body impurity
1) Mass Spectrometer Method：
As shown in fig. 6, ESI-MS of the support method synthesized in embodiment 5 for cloth：m/z 345.
2) hydrogen spectrum detection：
As shown in fig. 7, HNMR (400HMZ, the DMSO) δ (ppm) of support method synthesized in embodiment 5 for cloth impurity：
11.86,11.84 (s,1H, NH), 7.17 (s,1H, CH), 6.59 (s,1H, CH), 4.71 (s,1H, CH), 4.0-4.17 (m,2H,
CH2), 3.66-3.90 (m,3H, CH2, CH2), 3.34-3.43 (m,3H, CH3), 2.73,2.89 (d,1H, CH2), 2.37 (m,3H,
CH),1.58-1.82(t,1H,CH2), 0.99 (d,3H,CH3)。
As shown in figure 8, support method synthesized in embodiment 5 replaces cloth CNMR (400HMZ, DMSO) δ (ppm)：161.65,
157.63,152.38,151.73,121.37,116.18,102.25,100.82,53.23,41.64,34.08,31.03,
29.87,24.94,13.76。
From above-mentioned inspection result, the product as synthesized by embodiment 5 is that the support method to be protected of the invention replaces cloth impurity.
The corresponding data of embodiment 6-7 is consistent with embodiment 5, is not repeated to provide herein, and product synthesized by embodiment 6-7 is the present invention
The support method to be protected replaces cloth impurity.
(3) purity testing
Measuring method：HPLC analyses will be carried out as obtained in embodiment 5-7 by solid sample, by finding out support method for cloth impurity
Corresponding peak, and according to its purity of calculated by peak area.
Measurement result：As shown in table 2.
Table 2
| Embodiment is numbered | Support method replaces cloth impurity purity (weight %) |
| Embodiment 5 | 96.7 |
| Embodiment 6 | 96.8 |
| Embodiment 7 | 96.7 |
From table 2 it can be seen that there is more than 96.7% purity using the support method that the method for the present invention synthesizes for cloth impurity,
The purity requirement of standard items is complied fully with, and can be used as standard items.
(4) the support method synthesized by embodiment 5-7 (is for cloth impurity with the support method that embodiment 5 synthesizes for the application of cloth impurity
Example explanation)
Liquid chromatographic detection
Detection method：Reversed-phase liquid chromatography post (bonded silica gel such as C18, C8, phenyl is the analytical column of filler) is used, is detected
Device is UV-detector, with acetonitrile and trifluoroacetic acid cushioning liquid as mobile phase, is examined according to isocratic and gradient elution program
Survey.
Test condition：Use chromatographic column：Luna5u C18, particle diameter is 5um；Column temperature：30 DEG C, flow velocity：1.0ml/min, stream
Dynamic phase：The trifluoroacetic acid water of A 0.01%, the trifluoroacetic acid acetonitrile solution mobile phase according to the form below gradient elution programs of B 0.01%：
Test result：As shown in Figure 9 and Figure 10.
Test result：As shown in Figure 9 and Figure 10.Fig. 9 shows the liquid chromatogram for cloth impurity according to support method of the present invention；
Figure 10 to show and replace cloth liquid chromatogram for cloth impurity and Tuo Fa according to support method of the present invention.
As seen from Figure 10, can simultaneously detect that support method is replaced for cloth impurity and Tuo Fa by liquid phase chromatography detection method
Cloth, and both have good separating degree.Support method prepared by the present invention can be replaced cloth impurity as standard items, by liquid phase
Chromatographic detection can detect support method for cloth prepare during hold in the palm method for cloth impurity content, and other impurities content,
And then be conducive to carrying out qualitative and quantitative analysis for cloth for cloth intermediate and Tuo Fa to support method, cloth is replaced to support method preferably to improve
Quality.
The preferred embodiments of the present invention are the foregoing is only, is not intended to limit the invention, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (3)
1. a kind of support method replaces the synthetic method of cloth intermediate impurities, it is characterised in that the synthetic method is comprised the following steps：
Under the conditions of hydrogenation, in the presence of the first organic solvent and the first catalyst, by the support method for cloth intermediate and the first acid
Solution is contacted, and hydrogenation forms the intermediate impurities,
Wherein, the support method is as follows for the chemical structural formula of cloth intermediate：
The support method has structural formula in formula (I) for cloth intermediate impurities:
The hydrogenation condition includes：In a hydrogen atmosphere, pressure is 0.1-0.5MPa；Temperature be 60-90 DEG C under the conditions of, instead
Answer 5-10h；
First acid solution is 1.3-1.4 for the mol ratio of cloth intermediate with the support method:1；
First acid solution is inorganic acid and/or organic acid, and the organic acid is in glacial acetic acid, formic acid and trifluoroacetic acid
Plant or various, the inorganic acid is hydrochloric acid and/or sulfuric acid；
First organic solvent is one or more in methyl alcohol, ethanol, acetonitrile, ethylene glycol, acetone, propyl alcohol and isopropanol；
The catalyst is 3-5 for the mol ratio of cloth intermediate with the support method:100；
The catalyst is hydroxide palladium carbon, palladium carbon, one or more in platinum carbon.
2. synthetic method according to claim 1, it is characterised in that the hydrogenation condition includes：In hydrogen atmosphere
Under, pressure is 0.1-0.5MPa；Temperature be 70-75 DEG C under the conditions of, react 6-8h.
3. synthetic method according to claim 2, it is characterised in that be defined for cloth intermediate by every Ke Tuofa, described
The consumption of one organic solvent is 5-10ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510124650.1A CN104761556B (en) | 2015-03-21 | 2015-03-21 | Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510124650.1A CN104761556B (en) | 2015-03-21 | 2015-03-21 | Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104761556A CN104761556A (en) | 2015-07-08 |
| CN104761556B true CN104761556B (en) | 2017-06-23 |
Family
ID=53643696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510124650.1A Active CN104761556B (en) | 2015-03-21 | 2015-03-21 | Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104761556B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293682A (en) * | 2017-07-25 | 2019-02-01 | 重庆医药工业研究院有限责任公司 | A kind of support method is for cloth impurity and preparation method thereof |
| CN108948020B (en) * | 2018-07-03 | 2020-03-10 | 南京正大天晴制药有限公司 | Refining method of tofacitinib citrate |
| CN109608468B (en) * | 2018-12-29 | 2020-09-29 | 成都倍特药业股份有限公司 | Tofacitinib citrate impurity, and synthesis method and application thereof |
| CN110724146B (en) * | 2019-11-04 | 2022-03-11 | 四川大学 | Preparation method of tofacitinib citrate |
| CN113125587B (en) * | 2019-12-30 | 2022-05-24 | 成都百裕制药股份有限公司 | Tofacitinib intermediate and detection method of enantiomer thereof |
| CN112697912B (en) * | 2020-12-14 | 2021-09-21 | 上海博悦生物科技有限公司 | Method for detecting tofacitinib citrate intermediate and related impurities thereof |
| CN113376294A (en) * | 2021-08-16 | 2021-09-10 | 湖南九典制药股份有限公司 | Analysis method of ethyl cyanoacetate in tofacitinib citrate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3113621B2 (en) * | 1997-04-07 | 2000-12-04 | 三洋電機株式会社 | Cooking device |
| JP4078074B2 (en) * | 1999-12-10 | 2008-04-23 | ファイザー・プロダクツ・インク | Pyrrolo [2,3-d] pyrimidine compound |
| US7301023B2 (en) * | 2001-05-31 | 2007-11-27 | Pfizer Inc. | Chiral salt resolution |
| BRPI0613876A2 (en) * | 2005-07-29 | 2011-02-15 | Pfizer Prod Inc | pyrrolo [2,3-d] pyrimidine derivatives; its intermediates and synthesis |
| EP2938616A4 (en) * | 2012-12-28 | 2016-06-15 | Glenmark Pharmaceuticals Ltd | The present invention relates to process for the preparation of tofacitinib and intermediates thereof. |
-
2015
- 2015-03-21 CN CN201510124650.1A patent/CN104761556B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104761556A (en) | 2015-07-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104761556B (en) | Support method replaces cloth impurity and its synthetic method, and support method for the quality control method of cloth for cloth intermediate impurities, support method | |
| CN104356197B (en) | A kind of Carfilzomib intermediate and preparation method thereof, and a kind of preparation method of Carfilzomib | |
| CN107305202A (en) | The HPLC methods and impurity that analysis methanesulfonic acid pleasure is cut down for Buddhist nun and its preparation impurity make the purposes of reference standard | |
| CN103864774B (en) | A kind of preparation method of Lurasidone | |
| CN106153798B (en) | It is a kind of to be used to analyze the purposes for doing reference standard about the HPLC methods and these impurity of material for Buddhist nun's preparation according to Shandong for Buddhist nun and according to Shandong | |
| CN109824676A (en) | A kind of support method replaces preparation method and application of the cloth in relation to substance | |
| Sepe et al. | Callipeltins F–I: new antifungal peptides from the marine sponge Latrunculia sp. | |
| CN110305106A (en) | Related substance of a kind of amber love song Ge Lieting and preparation method thereof, analysis method and application | |
| CN103864646B (en) | The impurity preparation of rasagiline mesilate and the method for analysis | |
| CN106153797B (en) | It is a kind of to replace Buddhist nun's preparation Related substance method according to Shandong for Buddhist nun and according to Shandong | |
| CN110016035A (en) | Support method is for related substance of cloth and the preparation method and application thereof | |
| CN109400577B (en) | Rivaroxaban related compound and preparation method and application thereof | |
| CN106220634B (en) | The related substances F and G of pemetrexed disodium and its preparation and detection method | |
| CN104130207A (en) | Acotiamide hydrobromide hydrate and preparation method of crystal form thereof | |
| CN105440083B (en) | A kind of lobaplatin crystal, preparation method and medicinal application | |
| CN107290448A (en) | A kind of method of residual solvent in detection memantine | |
| Almiento et al. | Stereoselective synthesis and conformational analysis of unnatural tetrapeptides. Part 2 | |
| CN106543035A (en) | A kind of phenyl hydrazones compound, its preparation method, detection method and purposes | |
| CN105837514B (en) | The preparation method of Fimasartan impurity of the drug | |
| CN107778290B (en) | Impurity of quinoline derivative and preparation method thereof | |
| CN105481860B (en) | A kind of process for refining of Tadalafei I type crystal | |
| CN106661040A (en) | 6-aryl amino pyridone formamide compound crystal and preparation method therefor | |
| CN104262340A (en) | Method for preparing Tadalafil | |
| Balducci et al. | Synthesis and conformational preferences of unnatural tetrapeptides containing L-valine units | |
| CN110105323A (en) | Diarylpropane dimer analog derivative and its pharmaceutical composition and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |