CN109467552A - The preparation process of Aprepitant - Google Patents
The preparation process of Aprepitant Download PDFInfo
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- CN109467552A CN109467552A CN201910032530.7A CN201910032530A CN109467552A CN 109467552 A CN109467552 A CN 109467552A CN 201910032530 A CN201910032530 A CN 201910032530A CN 109467552 A CN109467552 A CN 109467552A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses the preparation process of Aprepitant, the compound A and compound B in the mixed solvent stirring and dissolving that n,N-Dimethylformamide and triethylamine is added first is obtained mixed solution by Setp1；Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 30~35 DEG C of temperature, is stirred to react 12~15h；Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product.The features such as the present invention by improving technique, optimization of C/C composites, the Aprepitant synthesis technology reaction condition provided is mild, at low cost, is fitted with large-scale industrial production；The Aprepitant finished product impurity content of synthesis is low, with high purity, and substantially increases the yield of Aprepitant.
Description
Technical field
The present invention relates to drug preparation technical fields, and in particular to a kind of preparation process of Aprepitant.
Background technique
Aprepitant is the selective high affinity antagonist of people's Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 neurokinin 1 (NK1) receptor.It is existing to other
Treatment chemotherapy causes the action target spot 5-hydroxytryptamine receptor 3 of the drug of nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV)
The affinity of (5-HT3), dopamine receptor and glucocorticoid receptor are low or without affinity.Aprepitant, which can inhibit cis-platinum, to be caused
Acute stage and period of delay vomiting, and enhance 5-HT3 receptor antagonist Ondansetron and glucocorticoid Dexamethasone on Cisplatin
The anti-emetic activity of caused vomiting.The structural formula of Aprepitant is as follows:
The synthetic method of main API in the prior art are as follows:
Impurity-removing method according to the literature includes being cleaned by ethyl acetate, methanol/ethyl acetate, acetone recrystallization,
Find that intermediate a residual quantity reaches 0.9% by repeating above-mentioned purifying process, intermediate b residual quantity 1%, even if by multiple
Purification effect is still unobvious, is unable to satisfy 0.1% or less API impurity residual.
Summary of the invention
The technical problems to be solved by the present invention are: that there are yields is lower for synthesis Aprepitant technique in the prior art, it is miscellaneous
Matter content is higher, purity is unsatisfactory for the technical problems such as requirement, and the present invention provides the preparations of the Aprepitant to solve the above problems
Technique.
The present invention is achieved through the following technical solutions:
The preparation process of Aprepitant, comprising the following steps:
Setp1 first stirs the compound A and compound B in the mixed solvent that n,N-Dimethylformamide and triethylamine is added
It mixes dissolution and obtains mixed solution；
Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；
Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；
Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 30~35 DEG C of temperature, is stirred to react 12~15h；
Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product；
Wherein, compound A and compound B reaction is as shown in formula (1):
Further, in the Setp1, the quality proportioning of the mixed solvent of n,N-Dimethylformamide and triethylamine is 1:
0.3。
Further, the mass values of the compound A and compound B are 1.3~2.0.
Further, the addition quality of the diisopropylamine lithium is the 1/3 of the quality summation of compound A and compound B；
The addition quality of the dithyl sulfate is the 0.05~0.10% of the quality summation of compound A and compound B；
Further, in the Setp1, the Solute mass fraction of mixed solution is 20%~45%, dithyl sulfate
The mass percentage concentration of the solution of dimethylbenzene is 75~80%.
Further, the drop rate of the solution of the dimethylbenzene of the dithyl sulfate is 25~30ml/min.
Further, in the Setp5, isolating and purifying concrete operation step includes:
Setp51, extraction and recovery: addition n-butanol, methylene chloride and water in the reaction solution that Setp4 is generated, agitated point
The organic layer obtained after layer processing is handled through absorbent drying again；
Dissolution: Setp52 the Aprepitant crude product is dissolved in acetone solvent；
Setp53, reflux decoloration: being added diatomite, be evaporated under reduced pressure, reflux decoloration 20min；
Crystallization: de-inking solution is added acetone washing and then the de-inking solution recycled after filtration treatment carries out by Setp54
Crystallization treatment；
Setp55 is filtered, washed: the feed liquid after crystallization being filtered, washed, Aprepitant wet product is obtained, washing uses third
The mixed solution of ketone and water；
Setp56 is dry: Aprepitant wet product being carried out vacuum drying treatment and obtains Aprepitant dry product, most afterwards through powder
Broken, screening, packaging obtain finished product.
Further, in the Setp51, n-butanol, methylene chloride quality proportioning be 1:3.
Further, in the Setp54, the specific operation method is as follows:
Firstly, filtered de-inking solution is warming up to 55 DEG C；
Secondly, under agitation, being added dropwise to the water that temperature is 20 DEG C, mixing speed 50r/ with the rate of 16ml/min
min；
Finally, solution is cooled to 0-5 DEG C, carries out crystallization 0.6h after completion of dropwise addition.
Further, in the Setp56,8h is dried under reduced pressure under the conditions of 40 DEG C of temperature.
The present invention has the advantage that and the utility model has the advantages that
For the present invention by improving technique, optimization of C/C composites, the Aprepitant synthesis technology reaction condition provided is mild, at low cost
The features such as, it fits with large-scale industrial production；The Aprepitant finished product impurity content of synthesis is low, with high purity, and substantially increases
The yield of Aprepitant.
Specific embodiment
To make the objectives, technical solutions, and advantages of the present invention clearer, below with reference to embodiment, the present invention is made
Further to be described in detail, exemplary embodiment of the invention and its explanation for explaining only the invention, are not intended as to this
The restriction of invention.
Embodiment 1
Present embodiments provide a kind of preparation process of Aprepitant, comprising the following steps:
Setp1 first stirs the compound A and compound B in the mixed solvent that n,N-Dimethylformamide and triethylamine is added
It mixes dissolution and obtains mixed solution；Wherein, the mass values of compound A and compound B are 1.3；In the mixed solvent N, N- dimethyl
The quality proportioning of the mixed solvent of formamide and triethylamine is 1:0.3, and the Solute mass fraction of mixed solution is 45%.
Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；Wherein, two is different
The addition quality of Propylamino lithium is the 1/3 of the quality summation of compound A and compound B.
Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；Dithyl sulfate
It is added the 0.05% of the quality summation that quality is compound A and compound B, the quality hundred of the solution of the dimethylbenzene of dithyl sulfate
Dividing concentration is 80%, and the drop rate of the solution of the dimethylbenzene of dithyl sulfate is 30ml/min.
Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 30 DEG C of temperature, is stirred to react 15h；
Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product；It isolates and purifies
Concrete operation step includes:
Setp51, extraction and recovery: being added n-butanol, methylene chloride and water in the reaction solution that Setp4 is generated, n-butanol and
The quality proportioning of methylene chloride is 1:3, stirs 60min under the conditions of 35 DEG C of temperature, and saturated brine is then added and carries out at layering
The organic layer obtained after reason, then handled through anhydrous magnesium sulfate absorbent drying；
Dissolution: Setp52 the Aprepitant crude product is dissolved in acetone solvent；
Setp53, reflux decoloration: being added 1% diatomite of Aprepitant crude product quality, be evaporated under reduced pressure, and reflux is de-
Color 20min；
Crystallization: de-inking solution is added acetone washing and then the de-inking solution recycled after filtration treatment carries out by Setp54
Crystallization treatment；It is as follows to crystallize concrete operations:
Firstly, filtered de-inking solution is warming up to 55 DEG C；
Secondly, under agitation, being added dropwise to the water that temperature is 20 DEG C, mixing speed 50r/ with the rate of 16ml/min
min；
Finally, solution is cooled to 0-5 DEG C, carries out crystallization 0.6h after completion of dropwise addition.
Setp55 is filtered, washed: the feed liquid after crystallization being filtered, and mixed by the quality proportioning of 1:0.6 using acetone and water
Filter cake is washed after even, obtains Aprepitant wet product；
Setp56 is dry: Aprepitant wet product being carried out vacuum drying treatment and obtains Aprepitant dry product, vacuum degree
0.05Mpa, drying temperature is 40 DEG C, drying time 12h, primary per stirring every other hour；Most afterwards through crushing, screening, packaging
Obtain finished product.
Wherein, compound A and compound B reaction is as shown in formula (1):
The final yield for obtaining Aprepitant is 96.7%, and purity (HPLC) is 99.8%, and largest single impurity content is
0.03%.
Embodiment 2
Present embodiments provide a kind of preparation process of Aprepitant, comprising the following steps:
Setp1 first stirs the compound A and compound B in the mixed solvent that n,N-Dimethylformamide and triethylamine is added
It mixes dissolution and obtains mixed solution；Wherein, the mass values of compound A and compound B are 2.0；In the mixed solvent N, N- dimethyl
The quality proportioning of the mixed solvent of formamide and triethylamine is 1:0.3, and the Solute mass fraction of mixed solution is 20%%.
Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；Wherein, two is different
The addition quality of Propylamino lithium is the 1/3 of the quality summation of compound A and compound B.
Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；Dithyl sulfate
It is added the 0.10% of the quality summation that quality is compound A and compound B, the quality hundred of the solution of the dimethylbenzene of dithyl sulfate
Dividing concentration is 75%, and the drop rate of the solution of the dimethylbenzene of dithyl sulfate is 25ml/min.
Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 35 DEG C of temperature, is stirred to react 12h；
Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product；It isolates and purifies
Concrete operation step includes:
Setp51, extraction and recovery: being added n-butanol, methylene chloride and water in the reaction solution that Setp4 is generated, n-butanol and
The quality proportioning of methylene chloride is 1:3；60min is stirred under the conditions of 35 DEG C of temperature, saturated brine is then added and carries out at layering
The organic layer obtained after reason, then handled through anhydrous magnesium sulfate absorbent drying；
Dissolution: Setp52 the Aprepitant crude product is dissolved in acetone solvent；
Setp53, reflux decoloration: being added 1% diatomite of Aprepitant crude product quality, be evaporated under reduced pressure, and reflux is de-
Color 20min；
Crystallization: de-inking solution is added acetone washing and then the de-inking solution recycled after filtration treatment carries out by Setp54
Crystallization treatment；It is as follows to crystallize concrete operations:
Firstly, filtered de-inking solution is warming up to 55 DEG C；
Secondly, under agitation, being added dropwise to the water that temperature is 20 DEG C, mixing speed 50r/ with the rate of 16ml/min
min；
Finally, solution is cooled to 0-5 DEG C, carries out crystallization 0.6h after completion of dropwise addition.
Setp55 is filtered, washed: the feed liquid after crystallization being filtered, and mixed by the quality proportioning of 1:0.6 using acetone and water
Filter cake is washed after even, obtains Aprepitant wet product；
Setp56 is dry: Aprepitant wet product being carried out vacuum drying treatment and obtains Aprepitant dry product, vacuum degree
0.05Mpa, drying temperature is 40 DEG C, drying time 12h, primary per stirring every other hour；Most afterwards through crushing, screening, packaging
Obtain finished product.
Wherein, compound A and compound B reaction is as shown in formula (1):
The final yield for obtaining Aprepitant finished product is 97.2%, and purity (HPLC) is 99.9%, and largest single impurity content is
0.03%.
Embodiment 3
Present embodiments provide a kind of preparation process of Aprepitant, comprising the following steps:
Setp1 first stirs the compound A and compound B in the mixed solvent that n,N-Dimethylformamide and triethylamine is added
It mixes dissolution and obtains mixed solution；Wherein, the mass values of compound A and compound B are 1.6；In the mixed solvent N, N- dimethyl
The quality proportioning of the mixed solvent of formamide and triethylamine is 1:0.3, and the Solute mass fraction of mixed solution is 34%.
Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；Wherein, two is different
The addition quality of Propylamino lithium is the 1/3 of the quality summation of compound A and compound B.
Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；Dithyl sulfate
It is added the 0.07% of the quality summation that quality is compound A and compound B, the quality hundred of the solution of the dimethylbenzene of dithyl sulfate
Dividing concentration is 76%, and the drop rate of the solution of the dimethylbenzene of dithyl sulfate is 28ml/min.
Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 33 DEG C of temperature, is stirred to react 14h；
Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product；It isolates and purifies
Concrete operation step includes:
Setp51, extraction and recovery: being added n-butanol, methylene chloride and water in the reaction solution that Setp4 is generated, n-butanol and
The quality proportioning of methylene chloride is 1:3；60min is stirred under the conditions of 35 DEG C of temperature, saturated brine is then added and carries out at layering
The organic layer obtained after reason, then handled through anhydrous magnesium sulfate absorbent drying；
Dissolution: Setp52 the Aprepitant crude product is dissolved in acetone solvent；
Setp53, reflux decoloration: being added 1% diatomite of Aprepitant crude product quality, be evaporated under reduced pressure, and reflux is de-
Color 20min；
Crystallization: de-inking solution is added acetone washing and then the de-inking solution recycled after filtration treatment carries out by Setp54
Crystallization treatment；It is as follows to crystallize concrete operations:
Firstly, filtered de-inking solution is warming up to 55 DEG C；
Secondly, under agitation, being added dropwise to the water that temperature is 20 DEG C, mixing speed 50r/ with the rate of 16ml/min
min；
Finally, solution is cooled to 0-5 DEG C, carries out crystallization 0.6h after completion of dropwise addition.
Setp55 is filtered, washed: the feed liquid after crystallization being filtered, and mixed by the quality proportioning of 1:0.6 using acetone and water
Filter cake is washed after even, obtains Aprepitant wet product；
Setp56 is dry: Aprepitant wet product being carried out vacuum drying treatment and obtains Aprepitant dry product, vacuum degree
0.05Mpa, drying temperature is 40 DEG C, drying time 12h, primary per stirring every other hour；Most afterwards through crushing, screening, packaging
Obtain finished product.
Wherein, compound A and compound B reaction is as shown in formula (1):
The final yield for obtaining Aprepitant finished product is 97.9%, and purity (HPLC) is 99.9%, and largest single impurity content is
0.02%.
In addition, the compound B is prepared by the following method acquisition: compound C and compound D is anti-in methanol solvate
Midbody compound B should be obtained, reaction temperature is 30 DEG C, it reacts as shown in formula (2):
Above-described specific embodiment has carried out further the purpose of the present invention, technical scheme and beneficial effects
It is described in detail, it should be understood that being not intended to limit the present invention the foregoing is merely a specific embodiment of the invention
Protection scope, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done should all include
Within protection scope of the present invention.
Claims (10)
1. the preparation process of Aprepitant, which comprises the following steps:
Setp1, the in the mixed solvent stirring that n,N-Dimethylformamide and triethylamine first is added in compound A and compound B are molten
Solution obtains mixed solution；
Setp2, in a nitrogen atmosphere, into mixed solution, addition diisopropylamine lithium is carried out uniformly mixed；
Setp3 under nitrogen protection, stirring condition, is added dropwise to the solution of the dimethylbenzene of dithyl sulfate；
Setp4 after completion of dropwise addition, under nitrogen protection, under the conditions of 30~35 DEG C of temperature, is stirred to react 12~15h；
Setp5 isolates and purifies the reaction product of the Setp4, obtains final Aprepitant finished product；
Wherein, compound A and compound B reaction is as shown in formula (1):
2. the preparation process of Aprepitant according to claim 1, which is characterized in that in the Setp1, N, N- dimethyl
The quality proportioning of the mixed solvent of formamide and triethylamine is 1:0.3.
3. the preparation process of Aprepitant according to claim 1, which is characterized in that the compound A's and compound B
Mass values are 1.3~2.0.
4. the preparation process of Aprepitant according to claim 3, which is characterized in that the addition of the diisopropylamine lithium
Quality is the 1/3 of the quality summation of compound A and compound B；The addition quality of the dithyl sulfate is compound A and chemical combination
The 0.05~0.10% of the quality summation of object B.
5. the preparation process of Aprepitant according to claim 4, which is characterized in that in the Setp1, mixed solution
Solute mass fraction is 20%~45%, and the mass percentage concentration of the solution of the dimethylbenzene of dithyl sulfate is 75~80%.
6. the preparation process of Aprepitant according to claim 1, which is characterized in that the dimethylbenzene of the dithyl sulfate
Solution drop rate be 25~30ml/min.
7. the preparation process of Aprepitant according to claim 1, which is characterized in that in the Setp5, isolate and purify tool
Body operating procedure includes:
Setp51, extraction and recovery: being added n-butanol, methylene chloride and water in the reaction solution that Setp4 is generated, at agitated layering
The organic layer obtained after reason is handled through absorbent drying again；
Dissolution: Setp52 the Aprepitant crude product is dissolved in acetone solvent；
Setp53, reflux decoloration: being added diatomite, be evaporated under reduced pressure, reflux decoloration 20min；
Crystallization: Setp54 the de-inking solution that de-inking solution is added acetone washing and then recycles after filtration treatment is crystallized
Processing；
Setp55 is filtered, washed: the feed liquid after crystallization is filtered, washed, obtains Aprepitant wet product, washing using acetone and
The mixed solution of water；
Setp56 is dry: Aprepitant wet product being carried out vacuum drying treatment and obtains Aprepitant dry product, most crushed, sieved afterwards
Divide, packaging obtains finished product.
8. the preparation process of Aprepitant according to claim 7, which is characterized in that in the Setp51, n-butanol, two
The quality proportioning of chloromethanes is 1:3.
9. the preparation process of Aprepitant according to claim 7, which is characterized in that in the Setp54, concrete operations
Method is as follows:
Firstly, filtered de-inking solution is warming up to 55 DEG C；
Secondly, under agitation, being added dropwise to the water that temperature is 20 DEG C, mixing speed 50r/min with the rate of 16ml/min；
Finally, solution is cooled to 0-5 DEG C, carries out crystallization 0.6h after completion of dropwise addition.
10. the preparation process of Aprepitant according to claim 7, which is characterized in that in the Setp56, in 40 DEG C of temperature
8h is dried under reduced pressure under the conditions of degree.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110746371A (en) * | 2019-11-20 | 2020-02-04 | 山东鲁抗医药股份有限公司 | Intermediate for preparing aprepitant and preparation method and application thereof |
| CN111943904A (en) * | 2019-05-15 | 2020-11-17 | 南京正大天晴制药有限公司 | Method for refining key intermediate of neurokinin 1 receptor antagonist |
| CN113582982A (en) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | Preparation method of NK1 receptor antagonist |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111943904A (en) * | 2019-05-15 | 2020-11-17 | 南京正大天晴制药有限公司 | Method for refining key intermediate of neurokinin 1 receptor antagonist |
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| CN113582982A (en) * | 2021-06-15 | 2021-11-02 | 山东罗欣药业集团股份有限公司 | Preparation method of NK1 receptor antagonist |
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Application publication date: 20190315 |