CN109293682A - A kind of support method is for cloth impurity and preparation method thereof - Google Patents
A kind of support method is for cloth impurity and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of luxuriant and rich with fragrance impurity compound A and preparation method thereof for replacing cloth of support, the impurity compound can be used for the Qualitative and quantitative analysis of impurity in tropsch imatinib production, so as to improve the quality standard of tropsch imatinib citrate, significance is provided for its safe medication.
Description
Technical field
The invention belongs to field of medicinal chemistry, and in particular to a kind of support method replaces the impurity and preparation method thereof of cloth.And its
The test method of cloth and its impurity is replaced for the purposes and Tuo Fa of cloth quality control reference standard as support method.
Background technique
Support method replaces cloth, chemical name are as follows: 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine -4-
Base) amino] piperidin-1-yl] -3- oxo propionitrile, CAS:477600-75-2, structural formula is as shown in Formula II.
Support method replaces cloth citrate (Tofacitinib citrate), trade name Xeljanz, chemical name are as follows: 3- [(3R,
4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidin-1-yl] -3- oxo propionitrile citric acid
Salt.CAS:540737-29-9 is 1/3 tyrosine protein of a kind of selectivity Janus kinases (JAK) developed by Pfizer company
Kinase inhibitor, on November 6th, 2012, Food and Drug Adminstration of the US (FDA) and Pfizer's joint declaration, citric acid support method
For cloth be approved for methotrexate for treatment response it is insufficient or in not tolerating to severe active rheumatoid arthritis (RA)
Adult patient.Currently, Japan, Switzerland, etc. states' approved support method for cloth citrate listing, be mainly used for treat adult rheumatoid
Property joint.Citric acid support method is shown in formula I for the structural formula of cloth.
Currently, having more documents and materials reports preparation and optimization method of the support method for cloth:
Chinese patent CN1729192: disclosing a kind of preparation method, as shown in Figure 1, formula IV is at Pd (OH)2The catalytic hydrogenation of/C
Under the conditions of remove benzyl protecting group, chromatograph to obtain formula III through column；III and cyano-acetic acid 2,5- dioxo-pvrrolidin -1- base
Ester occurs cyano-acetamide amination and reacts to obtain Formula II (i.e. support method is for cloth).2009, Price, K.E. et al. used cyanoacetic acid
Ethyl ester is improved as preparation process of the cyano-acetamide amination reaction reagent to Formula II.
Chinese patent CN101233138, CN1325498, CN102459270 disclose the support method of Formulas I for cloth citrate
Preparation method, react to obtain by Formula II and citric acid.
Chinese patent CN101233138 discloses another method that preparation support method replaces cloth citrate, as shown in Fig. 2, Formula V
At Pd (OH)2Reaction obtains formula III under the catalytic hydrogenation conditions of/C；III occurs cyano-acetamide amination and reacts to obtain Formula II (support method
For cloth)；II and citric acid can be obtained support method at salt and replace cloth citrate.
By the research to prior art technology, the preparation method of the present inventor's bibliography CN101233138, using V in Pd
(OH)2Reaction obtains formula III under the catalytic hydrogenation conditions of/C；III occurs cyano-acetamide amination reaction and is converted into Formula II, finally
Chinese holly hydrochloric acid support method is obtained at salt for cloth.
The product of chemical reaction is seldom the single compound with the enough purity for meeting pharmaceutical standards.Byproduct of reaction
And how much raw material used in the reaction exist in product mixtures.API support method for cloth prepare during certain
A little stages, it is often necessary to its purity is analyzed by HPLC, TLC or GC analytic approach, with measure its whether be suitable for continuing processing and
Finally it is used in drug.
Those skilled in the art replace the chemical structure and route of synthesis of cloth by understanding support method, find in formula III cyano second
During amidation generates II, aldol reaction can occur under alkalinity for bimolecular II, generate impurity formula A compound, this is miscellaneous
Matter does not have CAS registration number, has no the document report miscellaneous Quality Research and control application problem yet.
Summary of the invention
The technical problem to be solved by the present invention is to the controls by replacing cloth impurity to support method, improve the quality that support method replaces cloth
Standard provides important evidence for its safe medication.
The present invention is in order to solve the above technical problems, provide following technical solution:
Scheme 1: compound shown in a kind of formula A is provided:
。
Scheme 2: the preparation method of 1 compound A of scheme is provided, this method comprises the following steps:
(1) support method is mixed for cloth with organic solvent and/or organic base；
(2) control temperature is reacted 42-55 hours under the conditions of 80 to 95 DEG C；
(3) after the reaction was completed, it is slowly dropped to room temperature, reaction solution is poured into ice water, is sufficiently stirred, and water phase is gone in liquid separation；
(4) organic solvent dissolution is added in residue, and then static crystallization, filters to obtain crude product.
Scheme 3: 1 compound A of scheme is provided in control support method for the purposes in cloth quality.
Scheme 4: providing a kind of measurement support method for the method for cloth and its impurity compound A, this method comprises:
(1) a kind of support method is provided and makees test sample for cloth solution；
(2) provide it is a kind of containing the formula A of known quantity and/or characteristic close object solution make reference sample；
(3) with HPLC measurement (1) test sample and/or (2) reference product, determine support method for cloth sample Chinese style A presence or/
And amount.
The present invention provides a kind of isolated support methods to replace cloth impurity, i.e., the preparation method of formula A compound and replaces as support method
The purposes of cloth reference standard.Therefore, the present invention efficiently solves in the prior art lack to the control deficiency of single impurity
Place provides guarantee for further control support method for the quality of cloth.
Detailed description of the invention
Fig. 1 support method replaces the HPLC map of cloth
The HPLC map of Fig. 2 formula A compound
Fig. 3 support method replaces the HPLC map of cloth crude product compound of formula A content
Specific embodiment
In some embodiments, compound shown in formula A is provided.
In some embodiments, a kind of preparation method of formula A compound is provided, this method comprises the following steps:
(1) support method is mixed for cloth with organic solvent and/or organic base；Wherein organic solvent is C1-6Fatty alcohol, ethyl acetate,
Acetone, acetonitrile, preferably C1-6Fatty alcohol, more preferably ethyl alcohol；Organic base is pyridine, DBU, triethylamine or N, N- diisopropyl second
Amine, preferably DBU, organic base and support method are 5 ~ 10:1, preferably 7.5:1 for the molar ratio of cloth；
(2) control temperature is reacted under the conditions of 80 to 95 DEG C reacts 48-55 hours at 42-55 hours, preferably 85-95 DEG C, more
It is reacted 55 hours at preferably 85 DEG C；
(3) after the reaction was completed, it is slowly dropped to room temperature, reaction solution is poured into ice water, is sufficiently stirred, and water phase is gone in liquid separation；
(4) organic solvent dissolution is added in residue, and then static crystallization, filters to obtain crude product；
Preferably, this method further comprises the step of recrystallizing crude product, and the solvent of recrystallization is selected from C1-6Fatty alcohol, it is excellent
It is selected as methanol or ethyl alcohol, more preferably ethyl alcohol；
In some embodiments, the mass volume ratio of crude product and recrystallization solvent is 1:10；
In some embodiments, a kind of formula A compound is provided in control support method for the purposes in cloth quality；
In some embodiments, a kind of measurement support method is provided for the method for cloth and its impurity compound A, this method comprises:
(1) a kind of support method is provided for cloth sample；
(2) a kind of formula A compound containing known quantity and/or characteristic is provided and makees reference sample；
(3) amount for existing with chromatography determination support method for cloth sample compound of formula A or method being ask to replace cloth；
In some embodiments, the preferred high performance liquid chromatography of chromatography (HPLC) method.It measures and determines support method for cloth sample
Chinese style A closes the presence of object or/and the high performance liquid chromatography (HPLC) of amount generally comprises external standard method, internal standard method, the correction up factor
Principal component Self-control method etc., the knowledge of the specific operation process of these methods all this field routines.The determination includes
Object is closed in support method for the presence in cloth sample according to support method for the test result calculations or contrast A of cloth sample and reference sample
And/or amount.The calculating is the knowledge and calculation formula of this field routine.In the support method of actual production for detecting in cloth sample
The content that formula A closes object is limited the quantity in customary impurities hereinafter, being not more than 0.1%.
In some embodiments, the determination refers to the test knot that cloth test sample and reference sample are replaced according to support method
Fruit is calculated using the principal component Self-control method of external standard method, internal standard method or the correction up factor or judges that formula A compound is replaced in support method
Presence and/or amount in cloth sample；
In some embodiments, HPLC detection method uses octadecylsilane chemically bonded silica for filler, and Detection wavelength is
289nm selects Suitable flow that test is mutually made to meet custom requirements, chromatogram is recorded, with area normalization method calculated purity.
It should be understood that those skilled in the art based on content disclosed herein, the present invention can be carried out it is various without departing from
Various modifications and improvements in spirit and scope of the invention.They should all fall in the patent that claims hereof defines and protect
It protects in range.Moreover, it should be understood that embodiment provided herein is merely to illustrate the purpose of the present invention, and it should not be construed as this
The limitation of invention.
The following examples are not limited the scope of the invention for further understanding and illustrating the present invention.
General operation
The instrument that mass spectral analysis uses is 1200 highly effective liquid phase chromatographic system of Agilent, Agilent company G6410A series connection three
Weight level four bars mass spectrograph, ion source use electric spray ion source, positive ion mode.The HPLC eluent of shunting, allows about 1
μ g/ml enters mass spectrometric ion source.
The present invention uses following contracting word, and has following meaning:
Embodiment 1
Support method replaces the HPLC analysis method of cloth
This product about 10.0mg is taken, it is accurately weighed, it sets in 25ml measuring bottle, adding mobile phase, (- 0.3% ammonium formate solution of acetonitrile (takes formic acid
Ammonium 3.0g adds water about 1000ml to make to dissolve, filtration to get) (12:88)) about 10ml ultrasound makes to dissolve, mobile phase is diluted to quarter
Degree, shakes up, as test solution；It is tested according to high performance liquid chromatography (the 4th general rule 0512 of Chinese Pharmacopoeia version in 2015),
It is filler (Amethyst C18-H, 250mm × 4.6mm, 5 μm) with octadecylsilane chemically bonded silica；With 0.3% ammonium formate
Solution (take ammonium formate 3.0g, water about 1000ml is added to make to dissolve, filtration to get) is mobile phase A, and acetonitrile is Mobile phase B, and flow velocity is
1.0ml per minute carries out gradient elution according to following table；Detection wavelength is 289nm；Number of theoretical plate presses 3- hydroxyl-3-((3R, 4R)-
4- methyl -3-(methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) piperidin-1-yl) -2- (3S, 4R) -4- methyl -3-
(methyl (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) amino) piperidines -1- carbonyl) glutaronitrile peak calculate be not less than 5000.It takes pair
Liquid chromatograph is injected according to 20 μ l of solution, records chromatogram, adjusts detection sensitivity, keeps the peak height of principal component chromatographic peak about full
The 20% of range.It is accurate respectively again to measure test solution and each 20 μ l of contrast solution, liquid chromatograph is injected, chromatogram is recorded.
Deduct solvent blank peak and gradient elution peak, measure main peak area and each impurity peak area and, by area normalization method calculating, contain
Amount cannot be less than 90.0%.
Embodiment 2
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile is added in 50ml single port bottle, n-butanol 25ml is added, measures DBU 12ml, is sufficiently stirred, system is slow
Slow heating, temperature control react 55h to 85 DEG C, and TLC detection, raw material fundamental reaction is complete, stop reaction, cooled to room temperature will
Reaction solution pours into 150ml ice water, stirs 30min, and water phase is gone in liquid separation.It will be concentrated to get the dissolution of dope 25ml ethyl alcohol, it is quiet
Only crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.5g, yield: 50.0%.HPLC:80.5%, mass spectrum [ESI-MS,
M/z] in M+H+Peak is 625.
Embodiment 3
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 15ml, be sufficiently stirred, system slowly heats up, temperature control to 85
DEG C, 55h is reacted, TLC detection, raw material fundamental reaction is complete, stops reaction, and reaction solution is poured into 150ml by cooled to room temperature
In ice water, 30min is stirred, water phase is gone in liquid separation.It will be concentrated to get the dissolution of dope 25ml ethyl alcohol, static crystallization is for 24 hours.Decompression is taken out
Filter, obtained solid impurity crude product 2.5g, yield: 50.0%.HPLC:82.5%, M+H in mass spectrum [ESI-MS, m/z]+Peak is
625。
Embodiment 4
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 18ml, be sufficiently stirred, system slowly heats up, temperature control to 85
DEG C, 55h is reacted, TLC detection, raw material fundamental reaction is complete, stops reaction, and reaction solution is poured into 150ml by cooled to room temperature
In ice water, 30min is stirred, water phase is gone in liquid separation.It will concentration
The dissolution of dope 25ml ethyl alcohol is obtained, static crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.6g, yield
52.0%.HPLC:84.5%, M+H in mass spectrum [ESI-MS, m/z]+Peak is 625.
Embodiment 5
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 18ml, be sufficiently stirred, system slowly heats up, temperature control to 95
DEG C, 42h is reacted, TLC detection, raw material fundamental reaction is complete, stops reaction, and reaction solution is poured into 150ml by cooled to room temperature
In ice water, 30min is stirred, water phase is gone in liquid separation.It will concentration
The dissolution of dope 25ml ethyl alcohol is obtained, static crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.2g, receives
Rate: 44.0%.HPLC:83.6%, M+H in mass spectrum [ESI-MS, m/z]+Peak is 625.
Embodiment 6
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 18ml, be sufficiently stirred, system slowly heats up, temperature control to 85
DEG C, 48h is reacted, TLC detection, raw material fundamental reaction is complete, stops reaction, and reaction solution is poured into 150ml by cooled to room temperature
In ice water, 30min is stirred, water phase is gone in liquid separation.It will concentration
The dissolution of dope 25ml ethyl alcohol is obtained, static crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.8g, receives
Rate: 56.0%.HPLC:85.6%, M+H in mass spectrum [ESI-MS, m/z]+Peak is 625.
Embodiment 7
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 18ml, be sufficiently stirred, system slowly heats up, temperature control to 80
DEG C, 48h is reacted, TLC detection, raw material fundamental reaction is complete, stops reaction, and reaction solution is poured into 150ml by cooled to room temperature
In ice water, 30min is stirred, water phase is gone in liquid separation.It will concentration
The dissolution of dope 25ml ethyl alcohol is obtained, static crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.3g, receives
Rate: 46.0%.HPLC:82.5%, M+H in mass spectrum [ESI-MS, m/z]+Peak is 625.
Embodiment 8
At room temperature, 5g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines-is taken
1- yl] -3- oxo propionitrile be added 50ml single port bottle in, measure DBU 24ml, be sufficiently stirred, system slowly heats up, temperature control to 85
DEG C, 42h is reacted, not exclusively, the reaction was continued to 48h, and fundamental reaction is complete, stops reaction, naturally cools to room for TLC detection reaction
Temperature pours into reaction solution in 150ml ice water, stirs 30min, and water phase is gone in liquid separation.It is molten that dope 25ml ethyl alcohol will be concentrated to get
Solution, static crystallization is for 24 hours.Decompression filters, obtained solid impurity crude product 2.7g, yield: 54.0%.HPLC:85.3%, mass spectrum
M+H in [ESI-MS, m/z]+Peak is 625.
Embodiment 9
At room temperature, by 10g 3- [(3R, 4R) -4- methyl -3- [methyl (7H- pyrroles [2,3-d] pyrimidine-4-yl) amino] piperidines -
1- yl] -3- oxo propionitrile be added 100ml single port bottle in, measure 36ml DBU, be sufficiently stirred, system slowly heats up, and is heated to 85
DEG C, 48h is reacted, TLC detection is complete to raw material fundamental reaction, stops reaction, cooled to room temperature pours into reaction solution
In 300ml ice water, 30min is stirred, water phase is gone in liquid separation.The dissolution of dope 50ml ethyl alcohol will be obtained, static crystallization is for 24 hours.Decompression
It filters, obtains solid impurity crude product 6.1g.Yield: 61.0%, HPLC:85.6%, M+H in mass spectrum [ESI-MS, m/z]+Peak is
625。
Embodiment 10
2.5g impurity crude product is taken, is added in 50ml round-bottomed bottle, ethyl alcohol 25ml is measured, stirring is heated to flowing back, drop naturally after dissolved clarification
Temperature, static crystallization are stayed overnight, and are filtered, and 40 DEG C of obtained solid is dried under reduced pressure, and are repeated above-mentioned crystallization mode twice, are obtained product
2.05g, yield: 82%, HPLC 95.1%.M+H in [ESI-MS, m/z]+Peak is 625.
Embodiment 11
The impurity crude product 5g that will be obtained is added in 100ml round-bottomed bottle, measures ethyl alcohol 50ml, and stirring is heated to flowing back, after dissolved clarification
Temperature fall, static crystallization are stayed overnight, and are filtered, and 40 DEG C of obtained solid is dried under reduced pressure, and are repeated above-mentioned crystallization mode three times, are obtained product
3.9g, yield: 78%, purity: 95.8%.ESI-MS, m/z] in M+H+Peak is 625.
Embodiment 12
Support method is for cloth, the qualitative and quantitative analysis of formula A compound
A. chromatographic condition
Chromatographic column & filler: octadecylsilane chemically bonded silica is the chromatographic column (Waters of filler
Symmetry C18,5 μm, 4.6mm × 250mm)
Column temperature: 25 DEG C
Detection wavelength: 289nm
Sample volume: 20 μ l
Flow velocity: 1ml/min
Mobile phase: using 0.3% ammonium formate solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below ratio does linear gradient elution
(ratio is its volume ratio)
B. it prepares and identifies support method for cloth, the marker solution of formula A compound
Take support method for cloth respectively, formula A compound is appropriate, and respectively (- 0.3% ammonium formate solution of acetonitrile (takes formic acid with mobile phase
Ammonium 3.0g adds water about 1000ml to make to dissolve, filtration to get) (12:88)) about 10ml ultrasound makes to dissolve, mobile phase is diluted to quarter
Degree, shakes up to get each marker solution, each marker solution is injected separately into chromatographic column and is measured, and records chromatogram to get each
From retention time.Under above-mentioned chromatographic condition, support method is about that 19.946min(is shown in attached drawing 1 for the retention time of cloth)；Formula Aization
Close object retention time be about that 31.873 min(are shown in attached drawing 2), support method replace cloth crude product compound of formula A, HPLC content 0.12%,
(see attached drawing 3).Knowledge according to this field, it will be understood that support method, which is replaced reach between cloth, each substance of formula A compound, effectively divides
From, therefore the chromatographic condition can accurately identify support method for cloth and formula A compound.
Claims (8)
1. a kind of formula A compound:
。
2. the preparation method of formula A compound described in claim 1, described method includes following steps:
(1) support method is mixed for cloth with organic solvent and/or organic base；
(2) control temperature is reacted 42-55 hours under the conditions of 80-95 DEG C；
(3) after the reaction was completed, it is slowly dropped to room temperature, reaction solution is poured into ice water, is sufficiently stirred, and water phase is gone in liquid separation；
(4) organic solvent dissolution is added in residue, and then static crystallization, filters to obtain crude product.
3. method as claimed in claim 2, wherein organic solvent is C1-6Fatty alcohol, ethyl acetate, one of acetone or acetonitrile
Or it is several.
4. method as claimed in claim 2, wherein organic base is one in pyridine, DBU, triethylamine and n,N-diisopropylethylamine
Kind is several.
5. method as claimed in claim 2, the method further includes recrystallizing crude product.
6. method described in claim 5, wherein the solvent recrystallized is selected from C1-6Fatty alcohol.
7. the described in any item methods of claim 2-6, wherein organic base and support method replace the molar ratio of cloth for 5 ~ 10:1.
8. formula A compound described in claim 1 is in control support method for the purposes in cloth quality.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110606846A (en) * | 2019-07-30 | 2019-12-24 | 石药集团中奇制药技术（石家庄）有限公司 | Tofacitinib citrate impurity and analysis method and application thereof |
| CN113416195A (en) * | 2021-06-23 | 2021-09-21 | 合肥华方医药科技有限公司 | Preparation method of tofacitinib citrate condensation impurity and homologue thereof |
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| XIAO WU第: "Identification of related substances in tofacitinib citrate by LC-MS techniques for synthetic process optimization", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110606846A (en) * | 2019-07-30 | 2019-12-24 | 石药集团中奇制药技术（石家庄）有限公司 | Tofacitinib citrate impurity and analysis method and application thereof |
| CN113416195A (en) * | 2021-06-23 | 2021-09-21 | 合肥华方医药科技有限公司 | Preparation method of tofacitinib citrate condensation impurity and homologue thereof |
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