CN109851556A - Logical sequence cuts down the preparation method for Buddhist nun or its mesylate drug impurity - Google Patents
Logical sequence cuts down the preparation method for Buddhist nun or its mesylate drug impurity Download PDFInfo
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Abstract
The preparation method for Buddhist nun or its mesylate impurity is cut down the invention discloses logical sequence, the preparation method includes: using the chloro- 7- methoxy quinoline -6- amide of 4- as raw material, under the action of catalyst, substitution reaction is carried out with 4- amino -3- chlorophenate hydrochlorate, obtains 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide；The logical sequence is cut down for shown in Buddhist nun or its mesylate impurity such as formula (I), and the definition of R is detailed in specification.By the preparation method is that first passage chemical synthesis obtains logical sequence cuts down for Buddhist nun or its mesylate impurity.And it can be separated efficiently and rapidly to obtain target compound.
Description
Technical field
The invention belongs to but be not limited to pharmaceutical field, and in particular to logical sequence is cut down for technique in Buddhist nun or its mesylate production process
The preparation method of impurity.
Background technique
It is a kind of multiple target point tyrosine kinase inhibitor that methanesulfonic acid logical sequence, which is cut down for Buddhist nun, and targeting is in vascular endothelial growth factor
(VEFG) receptor VEGFR1, VEGFR2 and VEGFR3.Logical sequence, which is cut down, also to be inhibited to participate in pathologic vessels generation, tumour growth and cancer for Buddhist nun
Other tyrosine kinase inhibitors of disease progress, including fibroblast growth factor receptor (FGFR) 1-4, platelet-derived life
Growth factor receptor body α (PDGFR α), KIT and RET.In in vitro test, it is most effective to act on VEGFR2, VEGFR3, to VEGFR1
Function and effect are slightly weak, act on VEGFR2.VEGFR3 and are compared to for selectively high 10 times or so of FGFR1, PDGFR α/β.Methanesulfonic acid
Logical sequence cut down be for Buddhist nun a kind of oral administration molecular targeted agents.
It is 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- first that methanesulfonic acid logical sequence, which is cut down for the chemical name of Buddhist nun,
Oxygroup -6- quinoline formyl amine mesylate, structural formula are as follows:
Chinese patent CN106660964A reports methanesulfonic acid logical sequence and cuts down synthetic route for Buddhist nun, which is with the chloro- 7- of 4-
Methoxy quinoline -6- amide is SM1, in alkaline condition, dimethyl sulfoxide be under solvent with 4- amino -3- chlorophenate hydrochlorate
(SM2) substitution reaction generation logical sequence occurs to cut down for Buddhist nun's intermediate -1:4- (4- amino -3- chlorophenoxy) -7- methoxy quinoline -6- carboxylic
Sour amide (LFTN-1), intermediate -1 are condensed to yield logical sequence with phenyl chloroformate in n,N-Dimethylformamide and cut down among Buddhist nun
Body -2:(4- ((6- acid methylamide base -7- methoxy quinoline -4- base) oxygen) -2- chlorphenyl) phenyl carbamate (LFTN-2).
Intermediate -2 obtains intermediate -3:4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino using with cyclopropylamine generation substitution reaction
Phenoxy group) -7- methoxyl group -6- quinoline formyl amine (LFTN-3).Intermediate -3 is in the case where acetic acid is solvent, with methanesulfonic acid at salt, warp
Ethyl alcohol turns brilliant that methanesulfonic acid logical sequence is cut down for Buddhist nun's raw material finished product (LFTN).
In synthesis LFTN-1, two crucial impurity 4- (4- ((6- carbamoyl -7- methoxyl group quinolines can be generated
Quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxy quinoline -6- formamide (impurity A), 4- ((2- chloro-4-hydroxyl phenyl) ammonia
Base) -7- methoxy quinoline -6- formamide (impurity B) structural formula is as follows:
Although document discloses both process impurities or degradation impurity, they are during synthesizing methanesulfonic acid logical sequence is cut down for Buddhist nun
Obtain, however FDA official evaluate report or through pertinent literature retrieval a series of related methanesulfonic acids discuss method replace Buddhist nun impurity or
In metabolite, there is not associated description to above two impurity.
Methanesulfonic acid logical sequence is cut down in the control of impurity A, B to be of great significance for the research of Buddhist nun's synthesis technology.Through retrieving, do not find
There is the report of impurity A, the preparation of B correlation.
Summary of the invention
The present inventor have passed through a series of preparation method that researchs successfully develop impurity A, B, cut down for methanesulfonic acid logical sequence for Buddhist nun
It is effective control provide strong guarantee.
The present invention provides the logical sequences as shown in formula (I) to cut down the preparation method for Buddhist nun or its mesylate impurity, the preparation method
It include: using the chloro- 7- methoxy quinoline -6- amide of 4- as raw material, under the action of catalyst, with 4- amino -3- chlorophenate hydrochlorate
Substitution reaction is carried out, 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide is obtained；
R is hydrogen or following groups in formula (I):
In embodiments of the invention, when R is hydrogen in formula (I), then logical sequence shown in formula (I) is cut down for Buddhist nun or its mesylate
Impurity is 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide (impurity B)；When R is following in formula (I)
When group:
It is 4- (4- ((6- carbamoyl -7- methoxyl group quinoline that then logical sequence shown in formula (I), which is cut down for Buddhist nun or its mesylate impurity,
Quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxy quinoline -6- formamide (impurity A).
In embodiments of the invention, the logical sequence provided by the invention as shown in formula (I) is cut down for Buddhist nun or its mesylate impurity
Preparation method, further includes: by obtained 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide,
Under alkali effect, substitution reaction is carried out with the chloro- 7- methoxy quinoline -6- amide of 4-, obtains 4- (4- ((6- carbamoyl -7- first
Phenoxyl quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxy quinoline -6- formamide, then sterling solid is obtained through recrystallization.
In some embodiments of the present invention, wherein the substitution carried out with 4- amino -3- chlorophenate hydrochlorate is anti-
It should carry out in organic solvent, here, the organic solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran and dichloro
The mixture of one or more of methane, it is preferable that be ethyl alcohol.
In some embodiments of the present invention, wherein the catalyst is selected from potassium iodide, cuprous iodide, protobromide
One of copper and Potassiumiodate are a variety of, it is preferable that are potassium iodide.
In some embodiments of the present invention, wherein the substitution carried out with 4- amino -3- chlorophenate hydrochlorate is anti-
It should carry out under heating conditions, the temperature of the heating is 50 DEG C~90 DEG C, it is preferable that be 70 DEG C~80 DEG C.
In some embodiments of the present invention, after the substitution reaction carried out with 4- amino -3- chlorophenate hydrochlorate,
Directly cool down crystallization, filtering acquisition 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide sterling solid.
In some embodiments of the present invention, wherein the dosage of the 4- amino -3- chlorophenate hydrochlorate is that 4- is chloro-
1.0~5.0 times of 7- methoxy quinoline -6- amide mole, it is preferable that be 1.5 times.
In some embodiments of the present invention, the substitution reaction carried out with the chloro- 7- methoxy quinoline -6- amide of 4-
It is to be carried out in following reaction dissolvent: dimethyl sulfoxide and water, N,N-dimethylformamide and water, DMAC N,N' dimethyl acetamide
With water or N-Methyl pyrrolidone and water, it is preferable that be dimethyl sulfoxide and water；Here, dimethyl sulfoxide and water, N, N- bis-
The volume ratio of methylformamide and water, DMAC N,N' dimethyl acetamide and water or N-Methyl pyrrolidone and water be respectively 20:1~
2:1, it is preferable that be 9:1.
In some embodiments of the present invention, the substitution reaction carried out with the chloro- 7- methoxy quinoline -6- amide of 4-
Alkali used is selected from potassium hydroxide, potassium carbonate, potassium tert-butoxide, 11 carbon -7- alkene of triethylamine, pyridine and 1,8- diazabicylo
(DBU) one or more mixture in, it is preferable that be potassium hydroxide.
In some embodiments of the present invention, wherein 4- ((2- chloro-4-hydroxyl phenyl) the amino) -7- methoxyl group
The dosage of quinoline -6- formamide is 1.0~5.0 times of the chloro- 7- methoxy quinoline -6- amide mole of 4-, it is preferable that is 1.5
Times.
In some embodiments of the present invention, wherein the recrystallization are as follows: by 4- (4- ((6- carbamoyl -7- first
Phenoxyl quinoline -4- base) amino) -3- chlorophenoxy) and -7- methoxy quinoline -6- formamide be dissolved in ethyl acetate mixed with methanol it is molten
Then agent adds methyl tertiary butyl ether(MTBE) and is recrystallized；Here, the ethyl acetate and methanol mixed solvent, it is preferable that second
The volume ratio of acetoacetic ester and methanol is 1:1.
Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification
It obtains it is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by specification and power
Specifically noted structure is achieved and obtained in sharp claim.
Specific embodiment
Further describe technical solution of the present invention below by example, these embodiments be it is illustrative, do not constitute
Limiting the scope of the present invention.Those skilled in the art, under the teachings of the present invention, according to the prior art to wherein
Technical characteristic, which is equivalently replaced, to be still fallen in protection scope of the present invention.
1 compound of formula in following embodiment is bought from Tianjin method Moses Pharmaceutical Technology Co., Ltd, other raw materials and examination
Agent is unless otherwise specified ordinary commercial products.
The meaning of english abbreviation in the embodiment of the present invention:
11 carbon -7- alkene of DBU:1,8- diazabicylo, domestic, technical grade.
The testing conditions of HPLC are as follows:
Instrument and reagent
Acetonitrile rank: HPLC lot number: JA069330 producer: Merck
Perchloric acid rank: HPLC lot number: 20160201 producers: Shanghai examination
Mobile phase A: being added 1ml perchloric acid and 10ml acetonitrile, shake up in 990ml water, ultrasound to obtain the final product
Mobile phase B: being added 1ml perchloric acid and 100ml water, shake up in 900ml acetonitrile, ultrasonic 15min degassing to get.
The preparation of dilution: methanol
Chromatographic condition
1260 type high performance liquid chromatograph (number LC-037) producers: Agilent
Column model: CAPCELL PAK C18 chromatographic column producer: SHISEIDO
Chromatographic column specification: 4.6*150mm, 3um chromatographic column SN:A8AB02515
Flow velocity: 1.0ml/mi n Detection wavelength: 252nm
Column temperature: 25 DEG C of sample volumes: 10ul
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 85 | 15 |
| 35 | 60 | 40 |
| 42 | 0 | 100 |
| 45 | 0 | 100 |
| 45.01 | 85 | 15 |
| 50 | 85 | 15 |
Mass spectrograph is the triple level four bars LC1290-MS6460 of Agilent.
Embodiment 1
Methanesulfonic acid logical sequence is cut down for Buddhist nun's impurity -4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide
Preparation
By the chloro- 7- methoxy quinoline -6- amide (10g) of 4- and 4- amino -3- chlorophenate hydrochlorate (11.5g), potassium iodide
(25g) is added in reaction flask, is added under ethyl alcohol (150ml) stirring, is heated to flowing back, be stirred to react 20 hours, TLC monitoring reaction
(solvent is methylene chloride: methanol=10:1,4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- first completely
The Rf value 0.3 of amide), reaction solution is down to room temperature, water (450ml) is added stirring and crystallizing 2 hours, filters to obtain target product
13.5g (mass yield 135%), HPLC purity 98.7%.MS (ESI): 342.3 [M-H]-。
Embodiment 2
Methanesulfonic acid logical sequence is cut down for Buddhist nun's impurity -4- (4- ((6- carbamoyl -7- methoxy quinoline -4- base) amino) -3- chlorobenzene
Oxygroup) -7- methoxy quinoline -6- formamide preparation
It weighs 1ml purified water to be added in reaction flask, while weighing potassium hydroxide (0.71g) and being added in reaction flask, stirring is extremely
9ml DMSO is added, under stirring, by 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide in dissolved clarification
The chloro- 7- methoxy quinoline -6- amide (1.0g) of (2.18g) and 4- is added sequentially in reaction flask, is warming up to 110 DEG C and is stirred to react
2 hours, TLC monitors fully reacting, and (solvent was methylene chloride: isopropanol=20:1,4- (4- ((6- carbamoyl -7- first
Phenoxyl quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxy quinoline -6- formamide Rf value 0.2), it is added into reaction solution
3ml acetone and 27ml purified water are cooled to room temperature, stirring and crystallizing 2 hours, filter, filter cake ethyl acetate/methanol (volume ratio
It for 1:1) 20ml dissolution, is stirred at room temperature down, methyl tertiary butyl ether(MTBE) (60ml) is added and carries out crystallization, filters to obtain target product methanesulfonic acid
Logical sequence is cut down for Buddhist nun's impurity -4- (4- ((6- carbamoyl -7- methoxy quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxyl group
Quinoline -6- formamide (1.96g), yield 85.2%, HPLC purity 99%.MS (ESI): 544.3 [M+H]+。
Although embodiment disclosed by the application is as above, the content only for ease of understanding the application and use
Embodiment is not limited to the application.Technical staff in any the application fields, is taken off not departing from the application
Under the premise of the spirit and scope of dew, any modification and variation, but the application can be carried out in the form and details of implementation
Scope of patent protection, still should be subject to the scope of the claims as defined in the appended claims.
Claims (10)
1. the logical sequence as shown in formula (I) cuts down the preparation method for Buddhist nun or its mesylate impurity, comprising: with the chloro- 7- methoxy quinoline-of 4-
6- amide is raw material, under the action of catalyst, carries out substitution reaction with 4- amino -3- chlorophenate hydrochlorate, obtaining 4-, ((2- is chloro-
4- hydroxy phenyl) amino) -7- methoxy quinoline -6- formamide；
R is hydrogen or following groups in formula (I):
2. preparation method as described in claim 1, further includes: by obtained 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- first
Phenoxyl quinoline -6- formamide carries out substitution reaction with the chloro- 7- methoxy quinoline -6- amide of 4-, obtains 4- (4- under alkali effect
((6- carbamoyl -7- methoxy quinoline -4- base) amino) -3- chlorophenoxy) -7- methoxy quinoline -6- formamide, then pass through
Recrystallization obtains sterling solid.
3. preparation method as claimed in claim 1 or 2, wherein the substitution carried out with 4- amino -3- chlorophenate hydrochlorate
Reaction carries out in organic solvent, and here, the organic solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran and two
The mixture of one or more of chloromethanes, it is preferable that be ethyl alcohol.
4. preparation method as claimed in claim 1 or 2, wherein the catalyst is selected from potassium iodide, cuprous iodide, bromination
One of cuprous and Potassiumiodate is a variety of, it is preferable that is potassium iodide.
5. preparation method as claimed in claim 1 or 2, wherein the substitution carried out with 4- amino -3- chlorophenate hydrochlorate
Reaction carries out under heating conditions, and the temperature of the heating is 50 DEG C~90 DEG C, it is preferable that is 70 DEG C~80 DEG C.
6. preparation method as claimed in claim 5, wherein the substitution carried out with 4- amino -3- chlorophenate hydrochlorate is anti-
Ying Hou, directly cooling crystallization, filtering obtain 4- ((2- chloro-4-hydroxyl phenyl) amino) -7- methoxy quinoline -6- formamide sterling
Solid.
7. the preparation method as described in any one of claim 2 to 6, wherein the use of the 4- amino -3- chlorophenate hydrochlorate
Amount is 1.0~5.0 times of the chloro- 7- methoxy quinoline -6- amide mole of 4-, it is preferable that is 1.5 times.
8. the preparation method as described in any one of claim 2 to 6, wherein the described and chloro- 7- methoxy quinoline -6- amide of 4-
The substitution reaction of progress is carried out in following reaction dissolvent: dimethyl sulfoxide and water, N,N-dimethylformamide and water, N,
N- dimethyl acetamide and water or N-Methyl pyrrolidone and water, it is preferable that be dimethyl sulfoxide and water；Here, dimethyl is sub-
The volume ratio of sulfone and water, N,N-dimethylformamide and water, DMAC N,N' dimethyl acetamide and water or N-Methyl pyrrolidone and water
Respectively 20:1~2:1, it is preferable that be 9:1.
9. the preparation method as described in any one of claim 2 to 6, wherein the described and chloro- 7- methoxy quinoline -6- amide of 4-
Alkali used in the substitution reaction of progress is selected from potassium hydroxide, potassium carbonate, potassium tert-butoxide, triethylamine, pyridine and 1,8- diaza two
One or more mixture in 11 carbon -7- alkene of ring, it is preferable that be potassium hydroxide.
10. the preparation method as described in any one of claim 2 to 6, wherein the 4- ((2- chloro-4-hydroxyl phenyl) ammonia
Base) dosage of -7- methoxy quinoline -6- formamide is 1.0~5.0 times of the chloro- 7- methoxy quinoline -6- amide mole of 4-,
It preferably, is 1.5 times；
Or, the recrystallization are as follows: by 4- (4- ((6- carbamoyl -7- methoxy quinoline -4- base) amino) -3- chlorobenzene oxygen
Base) -7- methoxy quinoline -6- formamide is dissolved in ethyl acetate and methanol mixed solvent, then add methyl tertiary butyl ether(MTBE) into
Row recrystallization；Here, the ethyl acetate and methanol mixed solvent, it is preferable that the volume ratio of ethyl acetate and methanol is 1:1.
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| CN110117255A (en) * | 2019-06-10 | 2019-08-13 | 湖北扬信医药科技有限公司 | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof |
| CN113024459A (en) * | 2019-12-09 | 2021-06-25 | 重庆药友制药有限责任公司 | Alvatinib mesylate intermediate impurity and preparation method thereof |
| CN113045492A (en) * | 2021-03-26 | 2021-06-29 | 成都倍特药业股份有限公司 | Alvatinib mesylate impurity, and preparation method and detection method thereof |
| CN113533544A (en) * | 2020-04-16 | 2021-10-22 | 先声药业有限公司 | Method for detecting related substances of varlitinib mesylate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110117255A (en) * | 2019-06-10 | 2019-08-13 | 湖北扬信医药科技有限公司 | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof |
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| CN113533544A (en) * | 2020-04-16 | 2021-10-22 | 先声药业有限公司 | Method for detecting related substances of varlitinib mesylate |
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