CN102060815B - Preparation method of taxanes compound - Google Patents
Preparation method of taxanes compound Download PDFInfo
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- CN102060815B CN102060815B CN201010606309A CN201010606309A CN102060815B CN 102060815 B CN102060815 B CN 102060815B CN 201010606309 A CN201010606309 A CN 201010606309A CN 201010606309 A CN201010606309 A CN 201010606309A CN 102060815 B CN102060815 B CN 102060815B
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Abstract
The invention discloses a preparation method of a taxanes compound shown as the formula I in the specification, relating to the field of pharmaceutical chemistry. The preparation method comprises the following steps of: under the water isolating condition, with docetaxel as a raw material and benzene alcohol, ketons or ethers compounds as a solvent, dropwise adding dimethyl sulfate, carrying out the alkylation reaction for 0.5 to 10 hours at the temperature of 10 to 60 DEG C, controlling the PH value of the reaction solution between 7 and 8 by an alkalescent organic solvent during the alkylation reaction, and adding water for separate out crystals after the alkylation reaction, wherein the crystals are the compound shown as the formula I. In the preparation method, a one-step method is adopted to prepare the taxanes compound cabazitaxel shown as the formula I. The preparation method has the advantages of few reaction steps, mild reaction condition, short reaction time and high reaction efficiency, and is favorable for industrial production. Meanwhile, through controlling the dropping speed of an alkylating agent and the PH value of the reaction solution, the docetaxel can be prevented from decomposing and the purity of the reaction product can be enhanced.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate to a kind of preparation method of bearing taxanes specifically.
Background technology
Cabazitaxel (Jevtana); Belong to taxanes; Be by French Sanofi-Aventis drugmaker exploitation " gonadotropin releasing hormone (GnRH) " acceptor inhibitor class medicine; Being primarily aimed at the advanced prostate cancer patient, is a first and unique medicine that provides remarkable existence to benefit in the second line treatment of the intractable prostate cancer of transitivity hormone.On June 17th, 2010; FDA (Food and Drug Adminstration) (FDA) has ratified cabazitaxel (Jevtana) and prednisone (Prednisone) coupling treatment advanced prostate cancer; Be recommended in when using the invalid even state of an illness of advanced prostate cancer medicine Docetaxel commonly used to increase the weight of the first-selected medicine that is used to treat late period, hormone antagonist type prostate cancer clinically.
Cabazitaxel, molecular formula is C
45H
57NO
14, white crystals, water insoluble, dissolve in ethanol, chemistry [2aR-(2a α, 4 β, 4a β, 6 β by name; 9 α, (α R*, β S*), 11 α, 12 α, 12a α, 12b α)]-β-[[(1; 1-dimethyl-oxyethyl group) carbonyl] amino]-Alpha-hydroxy phenylpropionic acid [12b-acetyl oxygen-12-benzoyl oxygen-2a, 3,4,4a, 5,6,9; 10,11,12,12a, 12b-ten dihydros-4,6-dimethoxy-11-hydroxyl-4a, 8; 13,13-tetramethyl--5-oxo-7,11-methylene radical-1H-ring pentaene in the last of the ten Heavenly stems is [3,4] benzo [1,2-b] oxa-fourth ring-9-yl also] ester, structural formula is suc as formula shown in the I:
At present, the compound method that cabazitaxel is commonly used is to take off the acetyl baccatin III with female ring 10-under the effect of pyridine, to introduce chlorotriethyl silane as protective material, is reducing 4 through sodium hydride; Introduce methoxyl group for 6, again at DCC and DMAP, condensation under the effect of EtoAC; Alcoholysis obtains bullion under acidic conditions at last, and bullion obtains finished product with the organic solvent recrystallization again, like patent EP1020188; EP 1140064; US2002082291, US 6403634, WO 0041482 described compound method.
Yet above-mentioned compound method is to encircle 10-with mother to take off the acetyl baccatin III and prepare cabazitaxel through polystep reaction, and reaction time consumption is longer, and reaction efficiency is lower.In addition, when alcoholysis, produce a large amount of waste liquids and be unfavorable for environmental protection, and also be difficult for removing at purification step, product purity is lower.
Summary of the invention
In view of this, it is many to the present invention seeks to be directed against existing bearing taxanes cabazitaxel preparation method reactions step, and the defective of long reaction time provides a kind of preparation method who adopts single stage method to prepare bearing taxanes cabazitaxel.
For realizing the object of the invention, the present invention adopts following technical scheme:
The preparation method of compound c abazitaxel shown in a kind of formula I is under isolated moisture condition; With the Docetaxel is raw material, is solvent with benzene, alcohols, ketone or ether compound, dropwise adds methyl-sulfate; At 10～60 ℃ of following alkylated reaction 0.5～10h; Using weakly alkaline organic solvent control reacting liquid pH value during this time is 7～8, and reaction adds the elutriation crystalline substance after finishing, and the gained crystal is compound shown in the formula I.
Docetaxel has another name called docetaxel, Docetaxel, English name Docetaxel (DOC), its chemistry 5 β by name; 20-epoxy-1,2 α, 4; 7 β, 10 β, 13 α-hexahydroxy-Taxan-11-alkene-9-ketone-4; [(2 ' R, 3 ' S)-N-benzoyl-3-phenylisoserine ester, molecular formula is C to 10-diacetate esters-2-benzoic ether-13-
43H
53NO
14, molecular weight is 807.88, and white crystalline powder is soluble in organic solvents such as ethanol, acetone, ether, benzene, and structural formula is suc as formula shown in the II:
Docetaxel is semi-synthetic Japanese yew class antitumour drug, and it fundamentally " freezes " the cell inner frame be made up of microtubule, thus the anticancer division.Microtubule polymerization depolymerization then in a cell cycle promotes microtubule polymerization and hinders its depolymerization, thereby stops a large amount of cancer cells divisions, causes cancer cell death.
Isolated moisture condition according to the invention is protection of inert gas.Rare gas element is claimed rare gas again, comprises nitrogen, helium or argon gas etc., and this type gas does not have activity basically, is commonly used to do the anti-oxidation of protection gas.
Docetaxel is a white crystalline powder, and mixing with methyl-sulfate can't direct reaction, needs to use solvent.Docetaxel is soluble in organic solvents such as ethanol, acetone, ether, benzene, and therefore preparation method according to the invention is a solvent with benzene, alcohols, ketone or ether compound.Preferably, preparation method according to the invention is solvent with acetone.
Preferably, the said solvent load of preparation method according to the invention is that every 1g Docetaxel adds solvent 1～20mL.
Preparing method according to the invention is raw material with the Docetaxel, and alkylated reaction takes place under the methyl-sulfate effect, and the Wasserstoffatoms that is connected in the molecule on the Sauerstoffatom is replaced by alkyl, compound shown in the production I.
Preferably, at 30～40 ℃ of following alkylated reaction 4～5h.
Preferably, the mol ratio of said Docetaxel and said methyl-sulfate is 1: 1～1: 10.
Docetaxel is decomposing the generation by product under the vigorous reaction condition or under the strong alkaline condition easily, and too much by product is not only wasted reaction raw materials, reduced production efficiency, and influences the purity of reaction product.Preparing method according to the invention controls the condition of Docetaxel alkylated reaction through the pH value of rate of addition and the reaction solution of control methyl-sulfate, produces too much by product to avoid Docetaxel to decompose.
Preferably, methyl-sulfate rate of addition according to the invention is 0.0083mL/s～0.05mL/s.
The weakly alkaline organic solvent comprises pyridine compounds and their, triethylamine, sodium alkoxide and ammoniacal liquor; Wherein, Pyridine is common weakly alkaline organic solvent, and therefore weakly alkaline organic solvent according to the invention is preferably pyridine, and the method for said pyridine control reacting liquid pH value can be for dropwise adding.
Therefore bearing taxanes cabazitaxel is water insoluble shown in the formula I according to the invention, and preparation method according to the invention adds entry crystal is separated out after alkylated reaction finishes, and the gained crystal is cabazitaxel.
The very few crystal of amount of water can not be separated out fully, and amount of water too much has impurity to separate out.Preferably, the mass ratio of said Docetaxel and water is 1: 2～1: 5.
Cabazitaxel is water insoluble, dissolve in organic solvents such as methyl alcohol, ethanol, and therefore preparation method according to the invention comprises that also the gained crystal is with alcohol compound and water recrystallization purifying step.Said recrystallization purifying step is specially the gained crystal and adds with the alcohol compound dissolving, adds elutriation then and goes out crystal, and the gained crystal is the pure article of cabazitaxel.
Preferably, said alcohol compound add-on is that every 1g gained crystal adds alcohol compound 10～20mL.More preferably, said alcohol compound is a methyl alcohol.
Preferably, the mass ratio of gained crystal and water is 1: 1～1: 10.
In specific embodiments, adopt preparation method according to the invention to prepare bearing taxanes cabazitaxel, reaction efficiency is high, and yield reaches more than 90%, and purity is high, reaches 99%.
Preparing method according to the invention adopts single stage method to prepare bearing taxanes cabazitaxel, and reactions step is few, and reaction conditions is gentle, and bearing taxanes cabazitaxel preparation time is short, and reaction efficiency is high, helps suitability for industrialized production.Through the rate of addition of control alkylating agent and the pH value of reaction solution, avoid the Docetaxel decomposition simultaneously, improved the purity of reaction product.
Embodiment
The embodiment of the invention discloses a kind of preparation method of bearing taxanes.Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention is described through preferred embodiment, and the related personnel obviously can change or suitably change and combination method as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
For realizing the object of the invention, the present invention adopts following technical scheme:
The preparation method of bearing taxanes shown in a kind of formula I is under nitrogen or argon shield; With the Docetaxel is raw material; With benzene, alcohols, ketone or ether compound is solvent; Dropwise add the methyl-sulfate of 1～10 times of molar weight of said Docetaxel with the speed of 0.0083mL/s～0.05mL/s, at 10～60 ℃ of following alkylated reaction 0.5～10h, during to use weakly alkaline organic solvent control reacting liquid pH value be 7～8; Reaction adds the elutriation crystalline substance after finishing, and the gained crystal is compound bullion shown in the formula I.With compound bullion shown in the alcohol compound dissolving gained formula I, add elutriation afterwards and go out crystal then, the gained crystal is the pure article of compound shown in the formula I, and wherein, every 1g bullion adds the dissolving of 10～20mL alcohol compound, adds 1～10g elutriation crystalline substance.
Preparing method according to the invention adopts single stage method to prepare bearing taxanes cabazitaxel, and reactions step is few, and reaction conditions is gentle, and bearing taxanes cabazitaxel preparation time is short, and reaction efficiency is high, helps suitability for industrialized production.The present invention has simultaneously avoided the Docetaxel decomposition through the rate of addition of control methyl-sulfate and the pH value of reaction solution, has improved the purity of reaction product.
In order further to understand the present invention, the present invention is elaborated below in conjunction with embodiment.
Embodiment 1: the preparation of bearing taxanes according to the invention
Under nitrogen protection, 25.8g (0.032mol) Docetaxel is put in the 500mL there-necked flask, add 258ml acetone and be warming up to 35 ℃; Stirred solution drips 10g (0.08mol) methyl-sulfate with 0.0083mL/s speed then to clarification, drips pyridine simultaneously and keeps pH value 7～8 (the pyridine consumption is as the criterion with the value of PH); Behind 40 ℃ of reaction 5h, add the 60g elutriation and go out crystal, filter; Oven dry obtains the 24.1g of compound bullion shown in the formula I, and yield is 90.63%.The bullion of compound shown in the formula I 30 ℃～40 ℃ stirring and dissolving, adds 25g elutriation crystalline substance with 250mL methyl alcohol then, filters and collects crystal, gets compound 22.2g shown in the formula I after the oven dry, and yield is 92.12%, and purity is 99.3%.
Magnetic resonance detection result shows ,-R.M.N.
1H composes (300MHz; CDCl
3δ is unit with ppm; Coupling constant J is a unit with Hz): 1.14 (s, 3H:CH
3); 1.28 (s, 3H:CH
3); 1.38 (s, 9H:C (CH
3)
3); (1.74 s, IH :) at 1 OH; 1.94 (s, 3H:CH
3); 1.98 (s, 3H:CH
3); 2.20et 2.37 (2dd, J=16et 9, each 1H: at 14 CH
2); From 2.25 to 2.40 and 2.84 (2mt, each 1H: at 6 CH
2); 2.55 (s, 3H:COCH
3); (4.02 wide s, 1H :) at 10 OH; (4.04 d, J=7Hz, 1H :) at 3 H; 4.24 with 4.38 (2d, J=8.5, each 1H: at 20 CH
2); 4.54 (wide s, 1H: the H in 2 ' position); (4.96 wide d, J=9.5,1H :) at 5 H; 5.28 (wide d, J=10,1H: the H in 3 ' position); (5.38 wide s, 1H :) at 10 H; (5.44 dd, J=10 and 7.5,1H :) at 7 H; 5.52 (d, J=10,1H:CONH); (5.74 d, J=7,1H :) at 2 H; (6.34 wide t, J=9,1H :) at 13 H; From 7.25 to 7.40 (mt, 5H: the aromatic substance in 3 ' position); 7.50 (t, J=7.5,2H: a position OCOC
6H
5H); 7.63 (t, J=7.5,1H: contraposition OCOC
6H
5H); 8.12 (d, J=7.5,2H: ortho position OCOC
6H
5H).
Embodiment 2: the preparation of bearing taxanes according to the invention
Under argon shield, 77.5g (0.096mol) Docetaxel is put in the there-necked flask, add 77.5mL ethanol and be warming up to 35 ℃; Stirred solution drips 12.6g (0.10mol) methyl-sulfate with 0.05mL/s speed then to clarification, drips pyridine simultaneously and keeps pH value 7～8 (the pyridine consumption is as the criterion with the value of PH); Behind 10 ℃ of reaction 10h, add 300g water, separate out crystal; Filter, oven dry obtains formula I compound bullion 74.9g, and yield is 93.75%.The bullion of compound shown in the formula I is used the 1500mL dissolve with ethanol, adds 700g elutriation crystalline substance then, filters and collects crystal, gets compound 46.5g shown in the formula I after the oven dry, and yield is 93%, and purity is 99.2%.
Embodiment 3: the preparation of bearing taxanes according to the invention
Under argon shield, 40.4g (0.05mol) Docetaxel is put in the there-necked flask, add 800mL acetone stirred solution to clarification; Drip 63.0g (0.50mol) methyl-sulfate with 0.02mL/s speed then, drip pyridine simultaneously and keep pH value, behind 60 ℃ of reaction 3h 7～8 (the pyridine consumption is as the criterion with the value of PH); Add 100g water, separate out crystal, filter; Oven dry obtains formula I compound bullion 37.2g (0.046mol), and yield is 91.4%.The bullion of compound shown in the formula I is used the 500mL dissolve with methanol, adds 150g elutriation crystalline substance then, filters and collects crystal, gets compound 34.5g shown in the formula I after the oven dry, and yield is 92.8%, and purity is 99.3%.
The explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof.Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of claim of the present invention.
Claims (10)
1. the preparation method of compound shown in the formula I is characterized in that, under isolated moisture condition; With the Docetaxel is raw material, is solvent with benzene, alcohols, ketone or ether compound, dropwise adds methyl-sulfate; Alkylated reaction 0.5 ~ 10h under 10 ~ 60C, during to use weakly alkaline organic solvent control reacting liquid pH value be 7 ~ 8, reaction adds the elutriation crystalline substance after finishing; The gained crystal is compound shown in the formula I
2. according to the said preparation method of claim 1, it is characterized in that said solvent load is that every 1g Docetaxel adds solvent 1～20mL.
3. according to the said preparation method of claim 1, it is characterized in that reaction 4 ~ 5h under 30 ~ 40C.
4. according to the said preparation method of claim 1, it is characterized in that the mol ratio of said Docetaxel and said methyl-sulfate is 1:1 ~ 1:10.
5. according to the said preparation method of claim 1, it is characterized in that said methyl-sulfate rate of addition is 0.0083mL/s ~ 0.05mL/s.
6. according to the said preparation method of claim 1, it is characterized in that said weakly alkaline organic solvent is a pyridine.
7. according to the said preparation method of claim 1, it is characterized in that the mass ratio of said Docetaxel and water is 1:2 ~ 1:5.
8. according to the said preparation method of claim 1, it is characterized in that, also comprise with alcohol compound and water the gained crystal is carried out the recrystallization purifying step.
9. said according to Claim 8 preparation method is characterized in that, said alcohol compound add-on is that every 1g gained crystal adds alcohol compound 10 ~ 20mL.
10. said according to Claim 8 preparation method is characterized in that the mass ratio of gained crystal and water is 1:1 ~ 1:10.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI526437B (en) * | 2011-09-09 | 2016-03-21 | 台灣神隆股份有限公司 | Crystalline forms of cabazitaxel |
| CN103012328B (en) * | 2011-09-23 | 2015-03-04 | 复旦大学 | Method for preparing second-generation taxol anticancer drug Cabazitaxel |
| CN102408397B (en) * | 2011-10-19 | 2014-08-20 | 上海贝美医药科技有限公司 | New taxane derivative and preparation method thereof |
| CN102417491B (en) * | 2011-10-31 | 2013-11-06 | 江苏红豆杉生物科技有限公司 | Method for preparing cabazitaxel by taking 10-deacetylate-baccatin III as raw material |
| CN102532064B (en) * | 2011-12-13 | 2015-06-17 | 重庆泰濠制药有限公司 | Synthesis method of dimethoxy docetaxel |
| CN102675257B (en) * | 2012-05-10 | 2014-07-02 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| CN102746258B (en) * | 2012-07-25 | 2015-02-04 | 重庆泰濠制药有限公司 | Crystal forms of cabazitaxel and preparation method thereof |
| CN102898406B (en) * | 2012-11-02 | 2014-12-03 | 上海金和生物技术有限公司 | Cabazitaxel crystal and preparation method thereof |
| EP2917192B1 (en) | 2012-11-09 | 2019-03-20 | Intas Pharmaceuticals Limited | Process for the preparation of cabazitaxel and its intermediates |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6331635B1 (en) * | 1995-03-27 | 2001-12-18 | Aventis Pharma S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
| CN101857557A (en) * | 2009-04-09 | 2010-10-13 | 重庆泰濠制药有限公司 | Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof |
-
2010
- 2010-12-24 CN CN201010606309A patent/CN102060815B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6331635B1 (en) * | 1995-03-27 | 2001-12-18 | Aventis Pharma S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
| CN101857557A (en) * | 2009-04-09 | 2010-10-13 | 重庆泰濠制药有限公司 | Compound and preparation method thereof and midbody compound prepared with same and preparation method thereof |
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