CN106892883A - A kind of preparation method of Cabazitaxel intermediate - Google Patents
A kind of preparation method of Cabazitaxel intermediate Download PDFInfo
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- CN106892883A CN106892883A CN201710255150.0A CN201710255150A CN106892883A CN 106892883 A CN106892883 A CN 106892883A CN 201710255150 A CN201710255150 A CN 201710255150A CN 106892883 A CN106892883 A CN 106892883A
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- preparation
- compound
- raw material
- methyl
- cabazitaxel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Abstract
The invention discloses a kind of preparation method of Cabazitaxel intermediate, comprise the following steps：In solvent, in the presence of alkali, it is Cabazitaxel intermediate that raw material 1 and methylating reagent carry out methylation reaction to be obtained compound A, the compound A,
Description
Technical field
The present invention relates to a kind of medical preparation method, and in particular to a kind of preparation method of Cabazitaxel intermediate.
Background technology
Cabazitaxel is the Second line Drug of prostate cancer, is a kind of molecular design taxanes micromolecular compound.Card
The mechanism of anticancer action and feature of Ba Tasai are similar to docetaxel, belong to anti-micro-pipe class medicine.Cabazitaxel by with micro-pipe
Protein binding, promotes it to be assembled into micro-pipe, while these micro-pipes for having assembled can be prevented to disintegrate, makes microtubule stabilization, and then
Suppress cell mitosis, and Interphase cells function performance.The wherein synthesis of Cabazitaxel needs crucial compound in fact
A, compound A are：
The compound A of existing patent synthesis contains 15% three substitution impurity, and purity only has
83.2%, and the three substitutions impurity is difficult removes, yield only has 52.4%.
The content of the invention
The technical problems to be solved by the invention are low product yields, it is therefore intended that provide a kind of Cabazitaxel intermediate
Preparation method, solves the problems, such as that product yield is low.
The present invention is achieved through the following technical solutions：
A kind of preparation method of Cabazitaxel intermediate, comprises the following steps：In solvent, in the presence of alkali, by raw material 1
Carry out methylation reaction to obtain compound A, the compound A with methylating reagent is Cabazitaxel intermediate,
2- methyl -3- amylalcohols have been additionally added in the methylation reaction.
The preparation method of compound A is identical with existing preparation method in the present invention, and reaction principle is also identical, this invention
It is that a kind of material for being called 2- methyl -3- amylalcohols is added in reaction system, there was only the life of compound A during reaction
Into, suppress the generation of three substitution impurity, the generation of the impurity of difficult removal is reduced from root, so as to improve compound A's
Purity, improves yield.With cost advantage, it is adapted to industrialized production.
The reaction temperature of the methylation reaction is：- 40 DEG C~-50 DEG C.The solvent uses the anhydrous tetrahydro furan, alkali to be
Double (trimethyl silicon substrate) amido lithiums, methylating reagent is Methyl triflate.Double (trimethyl silicon substrate) amido lithiums and original
Material 1 mass ratio be：67.5%-68%, the Methyl triflate is with the mass ratio of raw material 1：66.0%-66.4%,
2- methyl -3- amylalcohols are with the mass ratio of raw material 1：3.8%-18.8%.In 30 minutes backward systems of the methylation reaction according to
Secondary addition hydrochloric acid solution, saturation NaHCO3 solution, system layering extract organic layer, organic layer be concentrated under reduced pressure to give white
Color solid, compound A is obtained after washing white solid with water.In the present invention to solvent, alkali, methylating agent it is preferred, alkali, methylate
Agent, 2- methyl -3- amylalcohols are preferred with the mass ratio of raw material 1 respectively, are on the basis of existing preparation method, by multiple
The preferred value that experiment draws.
The present invention compared with prior art, has the following advantages and advantages：
1st, the preparation method of a kind of Cabazitaxel intermediate of the invention, in reaction system add one kind be called 2- methyl-
The material of 3- amylalcohols, the generation for there was only compound A during reaction suppresses the generation of three substitution impurity, subtracts from root
Lack the generation of the impurity of difficult removal, so as to improve the purity of compound A, improve yield；
2nd, a kind of preparation method of Cabazitaxel intermediate of the invention has cost advantage, and the present invention is by improving product
Yield has saved various auxiliary agents in raw material and preparation process etc.；
3rd, a kind of preparation method preparation process is simple of Cabazitaxel intermediate of the invention, the present invention does not change existing
Preparation personnel will not be caused technical change by preparation principle.
Specific embodiment
To make the object, technical solutions and advantages of the present invention become more apparent, with reference to embodiment, the present invention is made
Further to describe in detail, exemplary embodiment of the invention and its explanation are only used for explaining the present invention, are not intended as to this
The restriction of invention.
Embodiment 1
A kind of preparation method of Cabazitaxel intermediate of the present invention, comprises the following steps：In solvent, in the presence of alkali,
It is Cabazitaxel intermediate that raw material 1 and methylating reagent carry out methylation reaction to be obtained compound A, the compound A,
2- methyl -3- amylalcohols have been additionally added in the methylation reaction.The reaction temperature of the methylation reaction is：-40
DEG C~-50 DEG C.The solvent uses anhydrous tetrahydro furan, and alkali is double (trimethyl silicon substrate) amido lithiums, and methylating reagent is trifluoro
Methyl mesylate.Double (trimethyl silicon substrate) amido lithium is with the mass ratio of raw material 1：67.5%-68%, the fluoroform sulphur
Sour methyl esters is with the mass ratio of raw material 1：66.0%-66.4%, 2- methyl -3- amylalcohols are with the mass ratio of raw material 1：3.8%-
18.8%.The methylation reaction sequentially adds hydrochloric acid solution, saturation NaHCO3 solution, system point for 30 minutes in backward system
Layer, extracts organic layer, and organic layer is carried out to be concentrated under reduced pressure to give white solid, and compound A is obtained after washing white solid with water.
The preparation method of compound A is identical with existing preparation method in the present invention, and reaction principle is also identical, this invention
It is that a kind of material for being called 2- methyl -3- amylalcohols is added in reaction system, there was only the life of compound A during reaction
Into, suppress the generation of three substitution impurity, the generation of the impurity of difficult removal is reduced from root, so as to improve compound A's
Purity, improves yield.With cost advantage, it is adapted to industrialized production.
Embodiment 2
Based on embodiment 1, the preferred Methyl triflate of the present embodiment is 66.2%, double (front threes with the mass ratio of raw material 1
Base silicon substrate) amido lithium is with the mass ratio of raw material 1：67.6%, 2- methyl -3- amylalcohols are with the mass ratio of raw material 1：3.8%, tool
Body implementation method is：5g raw materials 1 are added in reactor, anhydrous tetrahydro furan 50g, resulting solution is cooled to -40 DEG C~-50 DEG C,
Double (trimethyl silicon substrate) lithium amides of 3.38g are slowly dropped in reaction solution, it is after 30 minutes that 0.19g 2- methyl -3- amylalcohols is straight
Connect and be added to reaction system, 3.31g Methyl triflates are added drop-wise in reaction solution after being diluted with 10g tetrahydrofurans, the used time 15
Minute.After completion of dropping, continuation reacts 30min in -40 DEG C~-50 DEG C systems；1M hydrochloric acid solution 40g are added, 20min is stirred
Afterwards, saturated sodium bicarbonate solution 33g is added, 5min is stirred.Layering, organic layer is concentrated under reduced pressure, and obtains white solid, washes with water
Compound A4.05g can be obtained, containing three substitution impurity 3%, product yield is 77.12%.
Embodiment 3
As different from Example 2,2- methyl -3- amylalcohols are with the mass ratio of raw material 1：7.6%, compound can be obtained
A4.37, containing three substitution impurity 0.5%, yield is 83.51%.
Embodiment 4
As different from Example 2,2- methyl -3- amylalcohols are with the mass ratio of raw material 1：15%, compound can be obtained
A4.97g, containing three substitution impurity 0.01%, yield is：94.60%.
Embodiment 5
As different from Example 2,2- methyl -3- amylalcohols are with the mass ratio of raw material 1：18.8%, compound can be obtained
A4.54g, containing three substitution impurity 0.01%, yield 86.37%.
Integrated embodiment 2- embodiments 5, add the product yield after 2- methyl -3- amylalcohols to be above being produced in existing method
The product for going out, and it is 15% that 2- methyl -3- amylalcohols are optimal with the mass ratio of raw material 1.
Above-described specific embodiment, has been carried out further to the purpose of the present invention, technical scheme and beneficial effect
Describe in detail, should be understood that and the foregoing is only specific embodiment of the invention, be not intended to limit the present invention
Protection domain, all any modification, equivalent substitution and improvements within the spirit and principles in the present invention, done etc. all should include
Within protection scope of the present invention.
Claims (5)
1. a kind of preparation method of Cabazitaxel intermediate, comprises the following steps：In solvent, in the presence of alkali, by raw material 1 with
It is Cabazitaxel intermediate that methylating reagent carries out methylation reaction and obtains compound A, the compound A,
Characterized in that, being additionally added 2- methyl -3- amylalcohols in the methylation reaction.
2. the preparation method of a kind of Cabazitaxel intermediate according to claim 1, it is characterised in that it is described methylate it is anti-
The reaction temperature answered is：- 40 DEG C~-50 DEG C.
3. the preparation method of a kind of Cabazitaxel intermediate according to claim 2, it is characterised in that the solvent is used
Anhydrous tetrahydro furan, alkali is double (trimethyl silicon substrate) amido lithiums, and methylating reagent is Methyl triflate.
4. a kind of preparation method of Cabazitaxel intermediate according to claim 3, it is characterised in that double (front threes
Base silicon substrate) amido lithium is with the mass ratio of raw material 1：The mass ratio of 67.5%-68%, the Methyl triflate and raw material 1
For：66.0%-66.4%, 2- methyl -3- amylalcohols are with the mass ratio of raw material 1：3.8%-18.8%.
5. the preparation method of a kind of Cabazitaxel intermediate according to claim 4, it is characterised in that it is described methylate it is anti-
Answer and hydrochloric acid solution, saturation NaHCO3 solution are sequentially added within 30 minutes in backward system, system layering extracts organic layer, to organic
Layer is carried out being concentrated under reduced pressure to give white solid, and compound A is obtained after washing white solid with water.
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| CN201710255150.0A CN106892883A (en) | 2017-04-19 | 2017-04-19 | A kind of preparation method of Cabazitaxel intermediate |
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| CN201710255150.0A CN106892883A (en) | 2017-04-19 | 2017-04-19 | A kind of preparation method of Cabazitaxel intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516281A (en) * | 2011-10-20 | 2012-06-27 | 江苏红豆杉生物科技有限公司 | 10-deacetylbaccatin III and method for methoxylation of its derivative |
| CN103664837A (en) * | 2013-08-30 | 2014-03-26 | 北京阳光诺和药物研究有限公司 | Preparation method of high-purity cabazitaxel intermediate |
| WO2014072996A2 (en) * | 2012-11-09 | 2014-05-15 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
-
2017
- 2017-04-19 CN CN201710255150.0A patent/CN106892883A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102516281A (en) * | 2011-10-20 | 2012-06-27 | 江苏红豆杉生物科技有限公司 | 10-deacetylbaccatin III and method for methoxylation of its derivative |
| WO2014072996A2 (en) * | 2012-11-09 | 2014-05-15 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
| CN103664837A (en) * | 2013-08-30 | 2014-03-26 | 北京阳光诺和药物研究有限公司 | Preparation method of high-purity cabazitaxel intermediate |
Non-Patent Citations (2)
| Title |
|---|
| YUN-RONG JING ET AL.: "The synthesis of novel taxoids for oral administration", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 谢如刚主编: "《现代有机合成化学》", 31 January 2007, 华东理工大学出版社 * |
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Application publication date: 20170627 |
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