CN101353334A - Method for preparing docetaxel - Google Patents
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- CN101353334A CN101353334A CNA2008100702776A CN200810070277A CN101353334A CN 101353334 A CN101353334 A CN 101353334A CN A2008100702776 A CNA2008100702776 A CN A2008100702776A CN 200810070277 A CN200810070277 A CN 200810070277A CN 101353334 A CN101353334 A CN 101353334A
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Abstract
The invention relates to a new method for preparing Docetaxel which includes a new synthesizing method for forming 10-deacetyl baccatin III(II) for protecting C-7, C-10-carbobenzoxy by using the 10-deacetyl baccatin III(I) for reacting with a benzyl chloroformate compound, and a new method for forming a new compound of 2'-(1-ethoxyethyl)-N-debenzoyl-N-(boc)-C-7, C-10-II-X-CBZ-10-deacetyl paclitaxel(IV) by the reaction of (II) with 1-boc-(3R,4S)-4-phenyl azetidine-2-ketone(III) as well as the new compound. Simultaneously, the invention also provides a new method for preparing a new compound of 2'- (1-ethoxyethyl)-N-debenzoyl-N-(boc)-10-deacetyl paclitaxel(V) and a new method for removing the 1-ethoxyethyl from the (IV) to form the Docetaxel.
Description
Technical field
The present invention relates generally to from the precursor compounds and becomes docetaxel.More specifically, the present invention relates to and make docetaxel by following reaction:
Background technology
From 1992, since taxol is gone on the market by drugs approved by FDA, all kinds of treatment for cancer (LUNDBERGBB have been widely used in, RISOVIC V, RAMASWAMY M, et.al.A lipophilic paclitaxel derivative incorporatedin a lipid emulsion for parenteral administration, J Controlled Release, 2003,86 (1): 93-100).Except that being mainly used in treatment mammary cancer, ovarian cancer, to nonsmall-cell lung cancer (NSCLC), small cell lung cancer (SCLC) also has tangible curative effect during the taxol drug combination.Yuan etc. studies show that taxol has remarkable anti-human liver cancer activity (YUAN JH in addition, ZHANG RP, ZHANG RG, et al, Growth-inhibiting effoets of taxolon human liver carcinoma in vitro and in nude mice, World J Gastroenterol, 2000,6 (2): 210-215; YUAN JH, WANG XW, LUO D, et al, Antihepatoma activity of taxol, Acta Pharmaeol Sin, 2000,21 (5): 450-454).Ma Peiqi etc. to clinical application of taxol carried out summarizing (Ma Peiqi. taxol clinical application research progress, Chinese Medicine guide, 2004,6 (3): 210-213).But taxol is as the chemotherapeutic agent of injection, and it water-soluble very low has only 0.25 μ gmL
-1, seriously hindered its active better performance.For this reason, people have carried out the research of structure activity relationship and structure of modification to taxol.
People have obtained the derivative of a large amount of taxols in the structure of modification to taxol, filter out the higher taxanes antitumor drug of some activity, and wherein docetaxel is the most famous.Francoise-Gueritte (FRANCOISE-GUERITrEI.GenerM and recent aspects of the chemistry and structure-activity relationshipsof taxoids, Curr.Pharm.Design, 2001,7 (12): 1229-1249) drug efficacy study shows, skin carcinoma, head-neck malignant tumor are also had extremely strong antitumour activity.Qi Chuanmin etc. (Qi Chuanmin, Wang Yunfeng, Wang Liyuan, etc. the technical study of the synthetic docetaxel of four step method of purification, chemical science and technology, 2003,11 (2): 3-8) successfully synthesize docetaxel with 4 step method of purification.Compare with taxol, docetaxel has following several characteristics: 1. water-soluble 6～7 μ gmL
-1, be better than taxol slightly.2. activity is higher than taxol, and its stabilization to tubulin is better than taxol, and in the external antitumor activity research, its activity is 1.3-12 a times of taxol; Under identical toxicity dose, the anti-microtubule depolymerization ability of docetaxel is high about 1 times than taxol, in the intracorporeal active experiment all transplanted tumor strain activity also is better than taxol; The total medical expense of dosage is less than taxol.
Mostly docetaxel synthetic starting raw material is that with 10-deacetylate Baccatine III (I) be raw material at present, by following formula reaction carrying out (Ojima, I., J.Org.Chem., 1991,56,5263; Tetrahedron Lett., 1990,31,977; Tetrahedron Lett., 1993,34,4149-4152; J.Am.Chem.Soc., 1990,112,770; J.Am.Chem.Soc., 1988,110,278; Tetrahedron, 1988,44,5307; Jung, M.J., J.Org.Chem., 1991,56,1681; Tetrahedron, 1992,48,6985; Denis .J.-N., J.Am.Chem.Soc., 1988,110,5917; Holton, R.A., EP400,971,1990; Commercon, A., Tetrahedron Lett., 1992,33,5185):
This reaction has two very big defectives, and the first is being introduced protecting group 2,2, forms following by product during the 2-trichloroethyl chloroformate easily:
The appearance of by product (IX) not only influences reaction yield, and is difficult to compound (VII) is carried out purifying; It is two when being deprotection, and reaction conditions is violent, easily produces many side reactions.
Nicholas J. (US 5688977,1997) makes C-7 in the following way, C10-two-CBZ-10-deacetylate Baccatine III
The weak point of this reaction is: (a) temperature of reaction is too low, and energy consumption is big; (b) reaction yield only 80%; (c) because n-butyllithium alkalescence is extremely strong, make reaction preference relatively poor, even also seldom arrive highly purified C-7, C10-two-CBZ-10-deacetylate Baccatine III by column chromatography.Be necessary its technology is further studied for this reason.
Summary of the invention
An object of the present invention is to provide the preferable useful novel method of a kind of preparation docetaxel.
Further purpose of the present invention is that not providing to influence C-7, the novel method of C10-two-X-CBZ-10-deacetylate Baccatine III (II) 13-position hydroxyl when introducing protecting group.
Another object of the present invention provides 1-tertbutyloxycarbonyl-(3R; 4S)-4-phenyl azetidine alkane-2-ketone (III) is connected in the Baccatine III skeleton of having protected; and in deprotection reaction thereafter; adopt gentle mode to slough protecting group, to obtain highly purified docetaxel (VI).
A further object of the invention is that the mode with economy provides than more a kind of new synthetic method for preparing docetaxel and useful intermediates of high yield was arranged in the past.
Technical scheme of the present invention is as follows:
With the 10-deacetylate Baccatine III (I) shown in the following formula
With acylating agent
At 4-N, the N-lutidine carries out first esterification under existing, and forms the C-7 shown in the following formula, C10-two-X-CBZ-10-deacetylate Baccatine III (II)
Wherein, X is a substituting group, this substituting group can by company's phenyl ring 23 or 45 or the 6-position on substituting group, X=Me, Et waits alkyl; Also can be Cl, Br, NO
2, non-single alkyl such as alkoxyl group.When X=H, the existing report of this structure (US5688977,1997), but severe reaction conditions, side reaction is many, the invention provides the novel method of preparation (II).
(II) with the 1-tertbutyloxycarbonyl shown in the following formula-(3R, 4S)-carry out the esterification second time under 4-phenyl azetidine alkane-2-ketone (III)
Form the midbody compound (IV) shown in the following formula
(IV) by hydrogenolysis, slough 7, the X-CBZ on the 10-position forms intermediate (V) as follows:
(V) slough the 1-ethoxyethyl group by acidic conditions, form the target compound docetaxel (VI) shown in the following formula:
Below be described in detail as follows with regard to each reactions steps:
A.C-7, C-10-two-CBZ-10-deacetylate Baccatine III (II)
Esterification for the first time:
Undertaken by following condition:
10-deacetylate Baccatine III (I) and DMAP are dissolved in anhydrous tetrahydro furan, the amount of DMAP is 2.5-100 a times of 10-deacetylate Baccatine III (I) mole number, and the consumption of best DMAP is 5-10 a times of 10-deacetylate Baccatine III (I) mole number; Under-30 ℃-50 ℃ (optimum temps is-5 ℃-30 ℃) stirs, (amount of X-CBZ-Cl is 2.5-100 a times of 10-deacetylate Baccatine III (I) mole number with substituent X-CBZ-Cl is arranged on the phenyl ring, the consumption of best X-CBZ-Cl is 5-80 a times of 10-deacetylate Baccatine III (I) mole number) splash into wherein, the reinforced back that finishes was in 25-70 ℃ (optimum temps is 35-60 ℃) reaction 0.5-5 hour, reaction solution cool to room temperature after-filtration, after adding suitable quantity of water, extremely neutral with general acid-alkali accommodation pH value of solution, use dichloromethane extraction, merge organic layer, use anhydrous sodium sulfate drying, filter, boil off solvent, get C-7, C10-two-X-CBZ-10-deacetylate Baccatine III (II) oily crude product; This oily matter gets white solid, yield 85%, purity 97% through silica gel column chromatography (eluent ethylacetate and normal hexane).
B.2 '-and (1-ethoxyethyl group)-N-takes off benzoyl-N-(tertbutyloxycarbonyl)-C-7, and C-10-two-CBZ-10-removes acetyl taxol (IV)
Esterification for the second time:
Undertaken by following condition:
With C-7, C10-two-CBZ-10-deacetylate Baccatine III (II) is dissolved in anhydrous tetrahydro furan, stir down, (amount of NaH is C-7 with NaH, the 0.5-5 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number doubly, its best multiple is 1-2 times) add wherein, adding temperature is-15～-40 ℃, best adding temperature is-20～36 ℃, stir after 0.5 hour, (amount of two trimethyl silicane amine sodium is C-7 to drip content and be 2 moles the THF solution of two trimethyl silicane amine sodium, the 1-5 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number doubly, best multiple is 2.5-3.5 times), dropping temperature is-20 ℃～-50 ℃, optimum temps is-30 ℃～-40 ℃; Reaction times 1-20 hour, optimum reacting time was 3-8 hour.Reaction is finished, and adds the aqueous solution of saturated ammonium chloride, obtains containing the solution of midbody compound (IV).With ethyl acetate extraction 3 times, merge organic layer, with saturated nacl aqueous solution organic layer is washed the neutrality to pH, anhydrous sodium sulfate drying, filter, filtrate decompression distill oily matter, this oily matter through silica gel column chromatography (eluent ethylacetate and normal hexane) faint yellow solid, yield is more than 80%, and purity is more than 90%.
C.2 '-(1-ethoxyethyl group)-N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (V)
Take off the reaction of CBZ:
Midbody compound (IV) is dissolved in the mixing solutions that methyl alcohol and THF form, and solution proportion can be regulated, and wherein best proportioning is 2: 1; Adding 5% or 10% palladium-carbon, its consumption be midbody compound (IV) weight 1%～10%, temperature of reaction is a room temperature, normal pressure fed down hydrogen more than 0.5 hour, reacting liquid filtering is removed palladium-carbon, and the filtrate that must contain intermediate (V) is used for follow-up reaction; Or with the filtrate evaporate to dryness, purified handle faint yellow solid (V), yield 98%, purity 88%;
D.N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (VI)
Take off the reaction of 1-ethoxyethyl group:
N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and goes acetyl taxol (VI) to obtain by four kinds of modes:
(a) solid (V) is dissolved in the methyl alcohol and acetic acid (1: the 1) mixed solution of 6 times of volumes, under the ultrasonic wave effect, room temperature reaction is sloughed the 1-ethoxyethyl group more than 0.5 hour, obtains containing the solution of target compound docetaxel (VI); Solvent is flung in decompression, and the residue acetic acid ethyl dissolution uses sodium bicarbonate aqueous solution and water washing to neutral respectively, uses the anhydrous sodium sulfate drying organic layer, filters, and the pressure reducing and steaming solvent gets the class yellow solid, yield 98%, and purity is more than 85%.This solid gets docetaxel (VI) white solid through silica gel column chromatography (eluent ethylacetate and normal hexane), and yield is more than 70%, and purity is more than 99%.
(b) solid (V) is dissolved in the methyl alcohol and acetic acid (1: the 1) mixed solution of 6 times of volumes, sloughs the 1-ethoxyethyl group, obtain containing the solution of target compound docetaxel (VI) 30-70 ℃ (optimum temps is 45-55 ℃); Handle as stated above, get docetaxel (VI) white solid, yield is more than 60%, and purity is more than 97%.
(c) will take off reacting liquid filtering behind the CBZ, in filtrate, add acetic acid, its amount for the 0.5-5 of filtrate volume doubly, its best multiple be 1-3 doubly; After adding acetic acid, under the ultrasonic wave effect, room temperature reaction is sloughed the 1-ethoxyethyl group more than 0.5 hour, obtains containing the solution of target compound docetaxel (VI); Thereafter handle as stated above, get docetaxel (VI) white solid, yield is more than 70%, and purity is more than 97%.
(d) will take off reacting liquid filtering behind the CBZ, in filtrate, add acetic acid, its amount for the 0.5-5 of filtrate volume doubly, its best multiple be 1-3 doubly; After adding acetic acid, can slough the 1-ethoxyethyl group, obtain containing the solution of target compound docetaxel (VI) 30-70 ℃ (optimum temps is 45-55 ℃); Thereafter handle as stated above, get docetaxel (VI) white solid, yield is more than 60%, and purity is more than 95%.
Advantage of the present invention is as follows:
1. under the reaction starting material and reaction conditions that the present invention narrated; esterification can not influence the C-13 position hydroxyl of 10-deacetylate Baccatine III (I) for the first time; thereby can easily obtain highly purified C-7, C10-two-X-CBZ-10-deacetylate Baccatine III (II).
2. under the reaction starting material and reaction conditions that the present invention narrated; take off benzoyl-N-(tertbutyloxycarbonyl)-C-7 from 2 '-(1-ethoxyethyl group) N-; C-10-two-X-CBZ-10-goes acetyl taxol (IV) to slough protecting group X-CBZ on C-7 and the C-10 position O; and slough 1-ethoxyethyl group mild condition, reaction yield height from C-13 position O.
3. under the reaction starting material and reaction conditions that the present invention narrated, the cost of preparation docetaxel is lower, and quality is higher, is convenient to industrial production.
Embodiment
Embodiment 1:
A.C-7, C-10-two-CBZ-10-deacetylate Baccatine III (II)
Esterification for the first time:
10-deacetylate Baccatine III (I) and DMAP are dissolved in anhydrous tetrahydro furan, and the amount of DMAP is 5 times of 10-deacetylate Baccatine III (I) mole number; Under the stirring at room, chloroformic acid benzyl ester (for 15 times of 10-deacetylate Baccatine III (I) mole number) is splashed into wherein, the reinforced back that finishes is in 35-60 ℃, reacted 0.5 hour, reaction solution cool to room temperature after-filtration is after the adding suitable quantity of water, extremely neutral with general acid-alkali accommodation pH value of solution, use dichloromethane extraction, merge organic layer, use anhydrous sodium sulfate drying, filter, boil off solvent, get C-7, C10-two-X-CBZ-10-deacetylate Baccatine III (II) oily crude product; This oily matter gets white solid, yield 85%, purity 97% through silica gel column chromatography (eluent ethylacetate and normal hexane).
B.2 '-and (1-ethoxyethyl group)-N-takes off benzoyl N-(tertbutyloxycarbonyl)-C-7, and C-10-two-CBZ-10-removes acetyl taxol (IV)
Esterification for the second time:
With C-7, C10-two-CBZ-10-deacetylate Baccatine III (II) is dissolved in anhydrous tetrahydro furan, stir down, (amount of NaH is C-7 with NaH, 1 times of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number) adds wherein, adding temperature is-20 ℃, stir after 0.5 hour, (amount of two trimethyl silicane amine sodium is C-7 to drip content and be 2 moles the THF solution of two trimethyl silicane amine sodium, 1 times of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number), dropping temperature is-30 ℃; Reaction times, reaction was finished more than 3 hours, added the aqueous solution of saturated ammonium chloride, obtained containing the solution of midbody compound (IV).With ethyl acetate extraction 3 times, merge organic layer, with saturated nacl aqueous solution organic layer is washed the neutrality to pH, anhydrous sodium sulfate drying, filter, filtrate decompression distill oily matter, this oily matter through silica gel column chromatography (eluent ethylacetate and normal hexane) white solid, yield is more than 80%, and purity is more than 90%.
C.2 '-(1-ethoxyethyl group) N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (V)
Take off the reaction of CBZ:
(IV) is dissolved in methyl alcohol and THF2 with midbody compound: 1 mixing solutions of forming, and adding 5% or 10% palladium-carbon, temperature of reaction is a room temperature, normal pressure fed hydrogen down more than 0.5 hour, filtered, with the filtrate decompression evaporate to dryness, get faint yellow solid (V), yield 98%, purity 88%;
D.N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (VI)
Take off the reaction of 1-ethoxyethyl group:
(V) is dissolved in the methyl alcohol and acetic acid (1: the 1) mixed solution of 6 times of volumes, and under the ultrasonic wave effect, room temperature reaction is sloughed the 1-ethoxyethyl group more than 0.5 hour, obtains containing the solution of target compound docetaxel (VI); Solvent is flung in decompression, and the residue acetic acid ethyl dissolution uses sodium bicarbonate aqueous solution and water washing to neutral respectively, uses the anhydrous sodium sulfate drying organic layer, filters, and the pressure reducing and steaming solvent gets the class yellow solid, yield 98%, and purity is more than 85%.This solid gets docetaxel (VI) white solid through silica gel column chromatography (eluent ethylacetate and normal hexane), and yield is more than 70%, and purity is more than 99%.
Embodiment 2:
A.C-7, C-10-two-NO
2-CBZ-10-deacetylate Baccatine III (II)
Esterification for the first time:
10-deacetylate Baccatine III (I) and DMAP are dissolved in anhydrous tetrahydro furan, and the amount of DMAP is 5 times of 10-deacetylate Baccatine III (I) mole number; Under the stirring at room, chloroformic acid-4-nitrobenzyl ester (be 10-deacetylate Baccatine III (I) mole number 10 times) splashes into wherein; the reinforced back that finishes was reacted reaction solution cool to room temperature after-filtration 0.5 hour in 35-60 ℃; after adding suitable quantity of water, to neutral, use dichloromethane extraction with general acid-alkali accommodation pH value of solution; merge organic layer; use anhydrous sodium sulfate drying, filter, boil off solvent; get C-7, C10-two-NO
2-CBZ-10-deacetylate Baccatine III (II) oily crude product; This oily matter gets white solid, yield 90%, purity 97% through silica gel column chromatography (eluent ethylacetate and normal hexane).
B.2 '-(1-ethoxyethyl group)-N-takes off benzoyl N-(tertbutyloxycarbonyl)-C-7, C-10-two-NO
2-CBZ-10-goes acetyl taxol (IV) esterification for the second time:
Method gets white solid with embodiment 1B, and yield is more than 98%, and purity is more than 90%.
C.2 '-(1-ethoxyethyl group) N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (V)
Take off NO
2The reaction of-CBZ:
Method gets faint yellow solid (V), yield 98%, purity 88% with embodiment 1C;
D.N-takes off benzoyl N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (VI)
Take off the reaction of 1-ethoxyethyl group:
(V) is dissolved in the methyl alcohol and acetic acid (1: the 1) mixed solution of 6 times of volumes, sloughs the 1-ethoxyethyl group, obtain containing the solution of target compound docetaxel (VI) at 30-70 ℃; Handle as stated above, get docetaxel (VI) white solid, yield is more than 60%, and purity is more than 96%.
Embodiment 3:
A.C-7, C-10-two-Cl-CBZ-10-deacetylate Baccatine III (II)
Esterification for the first time:
10-deacetylate Baccatine III (I) and DMAP are dissolved in anhydrous tetrahydro furan, and the amount of DMAP is 5 times of 10-deacetylate Baccatine III (I) mole number; Under the stirring at room, chloroformic acid-4-benzyl chloride ester (be 10-deacetylate Baccatine III (I) mole number 10 times) splashes into wherein; the reinforced back that finishes was reacted reaction solution cool to room temperature after-filtration 0.5 hour in 35-60 ℃; after adding suitable quantity of water, to neutral, use dichloromethane extraction with general acid-alkali accommodation pH value of solution; merge organic layer; use anhydrous sodium sulfate drying, filter, boil off solvent; get C-7, C10-two-NO
2-CBZ-10-deacetylate Baccatine III (II) oily crude product; This oily matter gets white solid, yield 88%, purity 97% through silica gel column chromatography (eluent ethylacetate and normal hexane).
B.2 '-and (1-ethoxyethyl group)-N-takes off benzoyl N-(tertbutyloxycarbonyl)-C-7, and C-10-two-chloro-CBZ-10-goes acetyl taxol (IV) esterification for the second time:
Method gets white solid with embodiment 1B, and yield is more than 98%, and purity is more than 90%.
C.2 '-(1-ethoxyethyl group)-N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (V)
Take off NO
2The reaction of-CBZ:
Method gets faint yellow solid (V), yield 98%, purity 88% with embodiment 1C;
D.N-takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and removes acetyl taxol (VI)
Take off the reaction of 1-ethoxyethyl group:
To take off the reacting liquid filtering behind the Cl-CBZ, and add acetic acid in filtrate, its amount is 2 times of filtrate volume; After adding acetic acid, under the ultrasonic wave effect, room temperature reaction was sloughed the 1-ethoxyethyl group in 0.5 hour, obtained containing the solution of target compound docetaxel (VI); Thereafter handle as stated above, get docetaxel (VI) white solid, yield is more than 70%, and purity is more than 97%.
Claims (9)
1, the method for preparing docetaxel is characterized in that may further comprise the steps:
(a) with following formula 10-deacetylate Baccatine III (I)
With acylating agent
At 4-N, the N-lutidine carries out the esterification first time under existing, and forms the C-7 shown in the following formula, C10-two-X-CBZ-10-deacetylate Baccatine III (II)
Wherein, X is a substituting group, this substituting group by company's phenyl ring 23 or 45 or the 6-position on substituting group; (b) with the C-7 shown in the II formula, the 1-tertbutyloxycarbonyl shown in C10-two-X-CBZ-10-deacetylate Baccatine III (II) and the following formula-(3R, 4S)-carry out the esterification second time under 4-phenyl azetidine alkane-2-ketone (III)
Form midbody compound 2 '-(1-the ethoxyethyl group)-N-shown in the following formula and take off benzoyl-N-(tertbutyloxycarbonyl)-C-7, C-10-two-X-CBZ-10-removes acetyl taxol (IV)
(c) with the intermediate chemical combination shown in the IV formula by hydrogenolysis, slough 7, the X-CBZ on the 10-position forms intermediate 2 ' as follows-(1-ethoxyethyl group)-N-and takes off benzoyl-N-(tertbutyloxycarbonyl)-10-and remove acetyl taxol (V):
(d) intermediate shown in the V formula is sloughed the 1-ethoxyethyl group by acidic conditions, forms the target compound docetaxel (VI) shown in the following formula:
2. the method for claim 1, it is characterized in that: in the esterif iotacation step 10-deacetylate Baccatine III (I) and DMAP are dissolved in anhydrous tetrahydro furan THF in the first time, stir down X-CBZ-Cl is splashed into wherein, dropping temperature-30 ℃-50 ℃, reaction times is more than 0.5 hour, generation contains C-7, the solution of C10-two-X-CBZ-10-deacetylate Baccatine III (II); This solution after filtration, filtrate is regulated pH to neutral, dichloromethane extraction, anhydrous sodium sulfate drying filters, filtrate concentrates, concentrated solution is through column chromatography, highly purified C-7, C10-two-X-CBZ-10-deacetylate Baccatine III (II) white solid;
The amount of the DMAP of the described THF of being dissolved in is 2.5-100 a times of 10-deacetylate Baccatine III (I) mole number.
3. as claim 1 and 2 described methods, it is characterized in that: the benzene ring substitution group X=H of described acylating agent, Me, Et, sec.-propyl; Or be Cl, Br, NO
2, alkoxyl group.
4. method as claimed in claim 1 or 2, it is characterized in that: the C-7 that with mol ratio is 1: 2 in second time esterif iotacation step, C10-two-X-CBZ-10-deacetylate Baccatine III (II) and 1-tertbutyloxycarbonyl-(3R, 4S)-4-phenyl azetidine alkane-2-ketone (III) is dissolved in anhydrous tetrahydro furan, under the cooling and stirring, NaH is added wherein, after the stirring, drip the THF solution of two trimethyl silicane amine sodium, continue reaction, reaction is finished, and adds the aqueous solution of saturated ammonium chloride, obtain containing the solution of midbody compound (IV), this solution is through distillation, after handling, the purifying mode gets faint yellow solid (IV);
The amount that adds NaH is C-7, and the 0.5-5 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number times, adding temperature is-50～-15 ℃;
The amount of the THF solution of the two trimethyl silicane amine sodium of dropping is C-7 in two trimethyl silicane amine sodium, and the 1-5 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number times, dropping temperature is-50 ℃～-20 ℃, reaction times 1-20 hour.
5, method as claimed in claim 1 or 2, it is characterized in that: in hydrogenolysis, midbody compound (IV) is dissolved in the mixing solutions of methyl alcohol and THF, add palladium catalyst-carbon, stir and feed hydrogen down, slough intermediate (IV) C-7, X-CBZ on the O of C-10-position removes palladium-carbon with reacting liquid filtering, and the filtrate that must contain intermediate (V) is used for follow-up reaction; Or with the filtrate evaporate to dryness, purified handle faint yellow solid (V);
Palladium-carbon the consumption that adds be midbody compound (IV) weight 1%～10%, temperature of reaction is a room temperature, normal pressure fed hydrogen down more than 0.5 hour.
6. method as claimed in claim 1 or 2 is characterized in that: the described method that intermediate shown in (V) formula is sloughed the 1-ethoxyethyl group by acidic conditions is:
In the filtrate of containing intermediate (V), add filtrate volume 0.5-5 acetic acid doubly, under 30-70 ℃, slough the 1-ethoxyethyl group, obtain target compound docetaxel (VI);
Or, in the filtrate of containing intermediate (V), add filtrate volume 0.5-5 acetic acid doubly, under the ultrasonic wave effect, room temperature reaction is sloughed the 1-ethoxyethyl group more than 0.5 hour, obtains target compound docetaxel (VI);
Or (V) is dissolved in the methyl alcohol with solid, adds acetic acid and slough the 1-ethoxyethyl group under 30-70 ℃, obtains target compound docetaxel (VI);
Or (V) is dissolved in the methyl alcohol with solid, adds acetic acid under the ultrasonic wave effect, and room temperature reaction is sloughed the 1-ethoxyethyl group more than 0.5 hour, obtain target compound docetaxel (VI).
7. method as claimed in claim 2 is characterized in that: the consumption of described DMAP is 5-10 a times of 10-deacetylate Baccatine III (I) mole number; The consumption of X-CBZ-Cl is 10-80 a times of 10-deacetylate Baccatine III (I) mole number; Dropping temperature is-5 ℃-30 ℃; Reaction times 0.5-3 hour.
8. method as claimed in claim 4, in the esterif iotacation step, the amount that adds NaH is C-7 for the second time, the 1-2 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number times, adding temperature is-25～-40 ℃; The amount that drips the THF solution of two trimethyl silicane amine sodium is C-7, and the 2.5-3.5 of C10-two-X-CBZ-10-deacetylate Baccatine III (II) mole number times, dropping temperature is-30 ℃～-40 ℃, and the reaction times is 3-8 hour.
9. method as claimed in claim 5 is characterized in that: the ratio of the mixing solutions that methyl alcohol and THF form is 2: 1.
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| CNA2008100702776A CN101353334A (en) | 2008-09-10 | 2008-09-10 | Method for preparing docetaxel |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008100702776A CN101353334A (en) | 2008-09-10 | 2008-09-10 | Method for preparing docetaxel |
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| CN101353334A true CN101353334A (en) | 2009-01-28 |
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| CNA2008100702776A Pending CN101353334A (en) | 2008-09-10 | 2008-09-10 | Method for preparing docetaxel |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408397A (en) * | 2011-10-19 | 2012-04-11 | 上海贝美医药科技有限公司 | New taxane derivative and preparation method thereof |
| CN107141272A (en) * | 2017-06-30 | 2017-09-08 | 重庆市碚圣医药科技股份有限公司 | A kind of semi-synthetic docetaxel method and its intermediate |
| CN115650882A (en) * | 2022-11-14 | 2023-01-31 | 肇庆学院 | Docetaxel impurity and preparation method thereof |
-
2008
- 2008-09-10 CN CNA2008100702776A patent/CN101353334A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408397A (en) * | 2011-10-19 | 2012-04-11 | 上海贝美医药科技有限公司 | New taxane derivative and preparation method thereof |
| WO2013056662A1 (en) * | 2011-10-19 | 2013-04-25 | 上海贝美医药科技有限公司 | Novel taxane derivative and preparation method therefor |
| 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 |
| CN107141272A (en) * | 2017-06-30 | 2017-09-08 | 重庆市碚圣医药科技股份有限公司 | A kind of semi-synthetic docetaxel method and its intermediate |
| CN115650882A (en) * | 2022-11-14 | 2023-01-31 | 肇庆学院 | Docetaxel impurity and preparation method thereof |
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