CN107056767A - Method and intermediate for preparing water-soluble taxane analog derivative - Google Patents
Method and intermediate for preparing water-soluble taxane analog derivative Download PDFInfo
- Publication number
- CN107056767A CN107056767A CN201611101895.3A CN201611101895A CN107056767A CN 107056767 A CN107056767 A CN 107056767A CN 201611101895 A CN201611101895 A CN 201611101895A CN 107056767 A CN107056767 A CN 107056767A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- allyloxycarbonyl
- group
- benzyloxycarbonyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- IUUULXXWNYKJSL-UHFFFAOYSA-N CC(c(cc1)ccc1OC)O Chemical compound CC(c(cc1)ccc1OC)O IUUULXXWNYKJSL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention discloses a kind of method of the taxane derivatives of formula 2, and the taxane derivatives as formula 2 raw material or the compound of formula 1 and preparation method thereof of intermediate.
Description
The cross reference of related application
This application claims the priority for the Chinese patent application the 201510884378.7th submitted on December 4th, 2015,
The disclosure of the application quotes addition herein.
Technical field
The invention belongs to field of medicaments, it is related to the method and intermediate for preparing water-soluble taxane analog derivative, with
And the method for preparing the intermediate.
Background technology
Taxone (such as taxol and docetaxel) is excellent antineoplastic, is mainly used in treating late period
Breast cancer, oophoroma, non-small cell lung cancer and prostate cancer etc., also have to incidence cancer, stomach cancer, cancer of pancreas and melanoma etc.
There is certain curative effect.But, although the active anticancer of taxone is good, but their poorly water-soluble, the biological profit of oral administration
Expenditure is low, thus can only clinically pass through drug administration by injection.This kind of compound is commonly incorporated into non-ionic surface work when for clinic
The hydrotropies such as property agent such as Cremaphor EL or Tween-80, to be configured to injection.Regrettably, this kind of surface-active
Agent has the side effects such as vasodilation, blood pressure reduction, hepatotoxicity and serious allergic reaction so that taxone is facing
It is very restricted in bed application.In consideration of it, many medicine scholars try hard to change this shape by structure of modification in the world
State.
In the PCT/CN2015/073178 international patent applications that applicant of the present invention submitted for 2 months in 2015,
Report with the water-soluble taxane class prodrug of the structure of following formula 2.This kind of prodrug have good water solubility and with original
The consistent antitumor activity of medicine, so as to eliminate the toxic side effect brought in original taxanes injection by cosolvent:
Wherein R1For tert-butoxy or phenyl;R2For H or acetyl group;X is H, C1-6Alkyl or F;Y be F or by one or
The C of multiple F substitutions1-6Alkyl;N is 1,2,3,4,5 or 6;W is NR5R6A orR5、R6Be each independently H,
The C being optionally substituted by phenyl1-6Alkyl or C3-6Cycloalkyl;M is 0,1,2 or 3;A is pharmaceutically acceptable acid.
The method that the compound of following two formulas 2 is described in above-mentioned patent application:
First, using docetaxel or taxol as raw material, with amino isoxazolecarboxylic acid under triethylamine, pyridine or DMAP catalysis
Reaction, so that the compound of formula 2;
Second, using docetaxel or taxol as raw material, in compound (such as DCC, EDCI with carbodiimide structure
Deng) in the presence of, using organic bases such as DMAP, triethylamine or pyridines as catalyst and amino acid reaction, so that the change of formula 2
Compound.
Although the compound of formula 2 can be made in both approaches, due in the structure of docetaxel and taxol except
Outside the hydroxyl of 2 ' positions, in 7 and/or 10 there is also hydroxyl, thus 7 substitutions and/or 10 can be generated in preparation process
Substituted product and 2 ' positions and 7 substitution and/or 2 ' positions and 10 simultaneously-substituted two substitution products, even more multidigit simultaneously
The substitution product of point so that not only reduce the yield of end-product, also creates the impurity of a large amount of influence product qualities.
The content of the invention
According to the first aspect of the invention, the invention provides a kind of taxane derivatives for preparing and being represented by formula 2
Method:
Wherein:
R1For tert-butoxy or phenyl;
R2For H or acetyl group;
X is H, C1-6Alkyl or F;
Y is F or the C replaced by one or more F1-6Alkyl;
N is 1,2,3,4,5 or 6;
W is NR5R6A or
R5、R6The C for be each independently H, being optionally substituted by phenyl1-6Alkyl or C3-6Cycloalkyl;
M is 0,1,2 or 3;And
A is pharmaceutically acceptable acid,
Methods described includes:The compound of the formula 2 is prepared by raw material of the compound of formula 1:
Wherein:
R1As defined to the compound above to formula 2;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens.
Compared with the two methods disclosed in PCT/CN2015/073178 international patent applications, the present invention is carried
The method of confession produces few (or even not producing completely) impurity and by 2 ' caused by 7 substitutions and/or 10 substitutions
Position and 7 substitutions simultaneously and/or by 2 ' positions and 10 replace simultaneously caused by two substitution impurity, with higher yield and production
Product purity, and reaction condition is gentle, end-product (i.e. the compound of formula 2) is more easily separated.
According to the second aspect of the invention, the invention provides a kind of intermediate compound of the compound for formula 2
Thing, its pharmaceutically acceptable salt, polymorph or solvate, the midbody compound have formula 1 below:
Wherein,
R1For tert-butoxy or phenyl;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens.
According to the third aspect of the invention we, the invention provides a kind of method for the midbody compound for preparing above-mentioned formula 1,
Methods described includes:The compound of the formula 1 is prepared via following reaction scheme 2:
Reaction scheme 2
Embodiment
Definition
Term " halogen " used herein refers to fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
Term " C used herein1-6Alkyl " refers to the straight or branched alkyl of the saturation with 1-6 carbon atom, for example
Methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, just oneself
Base, isohesyl etc., preferably methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group, more preferably methyl, ethyl, propyl group or isopropyl
Base.
Term " C used herein3-6Cycloalkyl " refers to the monocyclic alkyl of the saturation with 3-6 carbon atom, such as ring third
Base, cyclobutyl, cyclopenta or cyclohexyl.
Term " benzyloxycarbonyl group " used herein refers to the benzyloxy being connected by carbonyl bond with the remainder of molecule.
Term " allyloxycarbonyl " used herein refers to the allyl oxygen being connected by carbonyl bond with the remainder of molecule
Base.
Term " pharmaceutically acceptable acid " used herein refers to pharmaceutically useful acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus
Acid, carbonic acid, acetic acid, propionic acid, methanesulfonic acid, lactic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid,
Citric acid or malic acid.
The compound of the present invention can exist in the form of its pharmaceutically acceptable salt, including its acid-addition salts and alkali addition
Salt.
Suitable acid-addition salts are formed by the acid for forming nontoxic salts.Example includes acetate, adipate, aspartic acid
Salt, benzoate, benzene sulfonate, bicarbonate/carbonate, disulfate/sulfate, borate, camsilate, citric acid
Salt, cyclamate, ethanedisulphonate, esilate, formates, fumarate, gluceptate, gluconate, Portugal
Glycuronate, hexafluorophosphate, hydrochloride/chloride, hydrobromate/bromide, hydriodate/iodide, isethionic acid
Salt, lactate, malate, maleate, malonate, mesylate, Methylsulfate, naphthoate, 2- naphthalene sulphurs
Sour hydrogen salt/the di(2-ethylhexyl)phosphate of hydrochlorate, nicotinate, nitrate, Orotate, oxalates, palmitate, embonate, phosphate/phosphor
Hydrogen salt, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluene fulfonate, trifluoro
Acetate, xinafoate etc..
Suitable base addition salts are formed by the alkali for forming nontoxic salts.Example includes aluminium salt, arginine salt, tardocillin
Salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt,
Sylvite, sodium salt, amino butanetriol salt, zinc salt etc..
The compound of the present invention can exist with its crystal form or polymorphic Form, and it can be single polycrystalline type thing or many
In a kind of mixture of the arbitrary proportion of polymorph.
The compound of the present invention can exist in the form of its solvate particularly hydrate, wherein the compound of the present invention
Include the polar solvent of the structural element as the compound lattice, such as water, ethanol, isopropanol, ethyl acetate or acetone.
The amount of polar solvent particularly water can exist with stoichiometric proportion or non-stoichiometric.
Using the compound of formula 1 as the compound of raw material formula 2
It is an object of the present invention to provide a kind of method for the taxane derivatives for preparing and being represented by formula 2:
Wherein:
R1For tert-butoxy or phenyl;
R2For H or acetyl group;
X is H, C1-6Alkyl or F;
Y is F or the C replaced by one or more F1-6Alkyl;
N is 1,2,3,4,5 or 6;
W is NR5R6A or
R5、R6The C for be each independently H, being optionally substituted by phenyl1-6Alkyl or C3-6Cycloalkyl;
M is 0,1,2 or 3;And
A is pharmaceutically acceptable acid,
Methods described includes:The compound of the formula 2 is prepared by raw material of the compound of formula 1:
Wherein:
R1As defined to the compound above to formula 2;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens.
According to one embodiment of the invention, X is H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or F.
According to one embodiment of the invention, Y is F or the methyl replaced by one or more F, ethyl, propyl group, different
Propyl group, butyl or isobutyl group.Preferably, Y is F, CF3、CH2F or CHF2。
According to one embodiment of the invention, R5、R6It is each independently H, methyl, ethyl, propyl group, isopropyl, fourth
Base, isobutyl group, benzyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
According to one embodiment of the invention, R3The benzyloxy carbonyl for acetyl group, optionally replaced by one or more chlorine
Base or allyloxycarbonyl.Preferably, R3For acetyl group, benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyl oxygen
Carbonyl.
According to one embodiment of the invention, work as R2During for H, R3For the benzyl optionally replaced by one or more halogens
Oxygen carbonyl or allyloxycarbonyl, are preferably the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more chlorine, more
Preferably benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl;Work as R2During for acetyl group, R3For acetyl
Base.
According to one embodiment of the invention, R4For the benzyloxycarbonyl group or alkene optionally replaced by one or more chlorine
Propylene carbonyl oxygen.Preferably, R4For benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl.
According to one embodiment of the invention, methods described includes:Compound using the formula 1 is raw material via following
Reaction scheme 1 prepares the compound of the formula 2:
Reaction scheme 1
Wherein R1、R2、R3、R4, W, X, Y and n as hereinbefore defined;And;
G is halogen or hydroxyl.
According to one embodiment of the invention, G is chlorine, bromine or hydroxyl.
Step 3:
Step 3 includes the protection group that 2 ' positions are removed from the compound of formula 1, so as to obtain the compound of formula 3.
Preferably, the reaction of step 3 is carried out in acid condition.
According to one embodiment of the invention, step 3 includes:
At a proper temperature in appropriate solvent, the compound of formula 1 is set to remove 2 ' positions in the presence of acid reagent
Protection group, so as to obtain the compound of formula 3.
Preferably, the temperature is 0-60 DEG C, preferably 20-35 DEG C.
Preferably, the solvent is water, methanol, ethanol, tetrahydrofuran, acetic acid or its combination, more preferably acetic acid or four
Hydrogen furans.
Preferably, the acid reagent is acetic acid or trifluoroacetic acid, more preferably trifluoroacetic acid.
Step 4:
Step 4 includes making the compound of formula 3 react with the compound of formula 8, so as to obtain the compound of formula 9.
According to one embodiment of the invention, the reaction of step 4 is in nitrogen-containing basic organic reagent or by nitrogenous base
Property organic reagent and the compound group with carbodiimide structure into mix reagent in the presence of carry out.
Preferably, the nitrogen-containing basic organic reagent is organic base, such as triethylamine, pyridine, DMAP, 4-PPY or its group
Close.
Preferably, the compound with carbodiimide structure is DCC, EDCI or its combination.
Preferably, by nitrogen-containing basic organic reagent with carbodiimide structure compound group into mix reagent
In, the mol ratio of the former with the latter is 1:(1-5).
According to one embodiment of the invention, when the G in the compound of formula 8 is halogen (such as chlorine or bromine), step 4
Carried out in the presence of nitrogen-containing basic organic reagent.
According to one embodiment of the invention, when the G in the compound of formula 8 is halogen (such as chlorine or bromine), step 4
Including:
At a proper temperature, in the presence of nitrogen-containing basic organic reagent, the compound of formula 3 and the compound of formula 8 are made
React in organic solvent, so that the compound of formula 9 is made.
Preferably, the temperature is -100-40 DEG C, more preferably preferably -60-0 DEG C, -30-0 DEG C.
Preferably, the mol ratio of the compound of formula 3, the compound of formula 8 and nitrogen-containing basic organic reagent is 1:(1-12.0):
(1-15.0), preferably 1:(1-4.0):(1-8.0).
Preferably, the organic solvent is dichloromethane, chloroform, 1,2- dichloroethanes or its combination.
According to one embodiment of the invention, when the G in the compound of formula 8 is hydroxyl, step 4 has in nitrogen-containing basic
Machine reagent with carbodiimide structure compound group into mix reagent in the presence of carry out.
According to one embodiment of the invention, when the G in the compound of formula 8 is hydroxyl, step 4 includes:
At a proper temperature, nitrogen-containing basic organic reagent with carbodiimide structure compound group into mixing
In the presence of reagent, the compound of formula 3 is set to be reacted in organic solvent with the compound of formula 8, so that the compound of formula 9 is made.
Preferably, the temperature is -60-40 DEG C, more preferably preferably 0-30 DEG C, 5-25 DEG C.
Preferably, the compound of formula 3, the compound of formula 8 and nitrogen-containing basic organic reagent are with having carbodiimide structure
Compound group into mix reagent mol ratio be 1:(1-12.0):(1-15.0), preferably 1:(1-4.0):(1-8.0), wherein
The mole of the mix reagent is in terms of the nitrogen-containing basic organic reagent.
Preferably, the organic solvent is dichloromethane, chloroform, 1,2- dichloroethanes or its combination.
Step 5:
Step 5 is included the compound hydrogenolysis of formula 9, so as to obtain the compound of formula 2.
Preferably, the hydrogenolysis is carried out in the presence of Pd reagents.
According to one embodiment of the invention, step 5 includes:
At a proper temperature, Pd reagents are added into the organic solvent of the compound containing formula 9, are led into reaction solution
Enter hydrogen, the compound of formula 2 is obtained after completion of the reaction.
Preferably, the temperature is -30-50 DEG C, preferably 10-35 DEG C.
Preferably, the organic solvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ethyl acetate, butyl acetate or its combination.
Preferably, the Pd reagents are Pd/C, PdCl2、Pd(PPh3)4Or its combination, more preferably Pd/C, more preferably
Amount containing Pd is 5-30% Pd/C, is most preferably the Pd/C that amount containing Pd is 5-10%.
Preferably, the amount of the Pd reagents is the 5-60%, preferably 10-30% of the amount of the compound of formula 9.
Preferably, the pressure for the hydrogen being passed through is 1-5atm, preferably 1-2atm.
It is miscellaneous caused by 7 substitutions and/or 10 substitutions the present invention overcomes being produced present in original route
Matter, by the substitution simultaneously of 2 ' positions and 7 and/or by 2 ' positions and 10 replace simultaneously caused by two substitution impurity and even more many
The defect of substituted impurity.There is higher yield and product purity using the compound of formula 2 made from the method for the present invention, and
The method reaction condition of the present invention is gentle, and end-product is more easily separated.
Midbody compound
Another object of the present invention is to provide a kind of midbody compound of the compound for formula 2, its pharmacy
Upper acceptable salt, polymorph or solvate, the midbody compound have formula 1 below:
Wherein,
R1For tert-butoxy or phenyl;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens.
According to one embodiment of the invention, R3The benzyloxy carbonyl for acetyl group, optionally replaced by one or more chlorine
Base or allyloxycarbonyl.Preferably, R3For acetyl group, benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyl oxygen
Carbonyl.
According to one embodiment of the invention, R4For the benzyloxycarbonyl group or alkene optionally replaced by one or more chlorine
Propylene carbonyl oxygen.Preferably, R4For benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl.
According to one embodiment of the invention, the compound of formula 1 of the invention is selected from:
The compound of above-mentioned formula 1 acts not only as raw material or reaction intermediate to prepare the water-soluble Japanese yew of above-mentioned formula 2
Alkane derivative, the course of reaction for the compound for being also used as reference substance to monitor formula 2, is also used as detection and contains
The bulk drug of the compound of formula 2 or the impurity reference substance of pharmaceutical preparation.
The preparation of midbody compound
A further object of the present invention is to provide a kind of method for the midbody compound for preparing above-mentioned formula 1.Methods described
Including:Via the compound of the following formula 1 of reaction scheme 2:
Reaction scheme 2
Wherein R1、R2、R3And R4As hereinbefore defined.
Step 1:
Step 1 includes the compound of formula 5 being acylated with acylating reagent, with 7 of the compound of protecting formula 5 and/or
The hydroxyl of 10, so as to obtain the compound of formula 6.
According to one embodiment of the invention, the acylating reagent is benzyl chloroformate, 3- Chlorobenzyl chloroformates, 4-
Chlorobenzyl chloroformate or allyl chlorocarbonate.
According to one embodiment of the invention, US6307071 patents or Xu Shaojie are referred to,《Docetaxel
Synthesis technique》, scientific and technological Leader 2010 (28) 13:The method reported in 82-86 carries out the reaction of step 1.
Step 2:
Step 2 includes making the compound of formula 6 occur condensation reaction with the compound of formula 7, so as to obtain the compound of formula 1.
Preferably, the reaction of step 2 is carried out in the basic conditions.
According to one embodiment of the invention, step 2 includes:
At a proper temperature in organic solvent, make the compound of formula 6 with the compound of formula 7 in the organic examination of nitrogen-containing basic
Reacted in the presence of agent and compound with carbodiimide structure, so that the compound of formula 1 is made.
Preferably, the temperature is 30-80 DEG C, more preferably 40-60 DEG C.
Preferably, the nitrogen-containing basic organic reagent is organic base, such as triethylamine, pyridine, DMAP, 4-PPY or its group
Close.
Preferably, the compound with carbodiimide structure is DCC, EDCI or its combination.
Preferably, the organic solvent is dichloromethane, chloroform, 1,2- dichloroethanes, toluene or its combination.
According to one embodiment of the invention, the method for being referred to US20040073044 patent reports is carried out
The reaction of step 2.
The method technique of the compound of above-mentioned formula 1 is simple, and reaction condition is gentle, is adapted to industrialized production.
Embodiment
In order that the purpose of the present invention and technical scheme are clearer, the preferred embodiments of the present invention are carried out below detailed
Description.To illustrate that:Following examples are served only for that the present invention is further detailed, and it is not intended that to this hair
The limitation of bright protection domain.Those skilled in the art according to the present invention the above make some it is nonessential improvement and
Adjustment belongs to protection scope of the present invention.Also, NM specific experiment method in the following example, according to conventional reality
Proved recipe method is carried out.
Abbreviation herein has following meanings:
DMAP | 4-N, N- dimethylamino naphthyridine |
DCC | Dicyclohexylcarbodiimide |
EDCI | 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride |
4-PPY | 4- pyrollidinopyridines |
The preparation of the compound of formula 6
Embodiment 1
Benzyloxycarbonyl group -10- deacetyl baccatins the III of 7,10-O- bis- preparation
At room temperature, 10- deacetyl baccatins III (13.0g, 23.9mmol) is dissolved in anhydrous tetrahydro furan (180mL),
DMAP (29.1g, 0.239mol) is added, 40-50 DEG C is heated to.Add the nothing containing benzyl chloroformate (40.7g, 0.239mol)
Water tetrahydrofuran solution (80mL), monitors through HPLC and reacts.After completion of the reaction, filter, by filtrate decompression concentration to remove solvent,
Residue ethyl acetate (300mL) is dissolved, washed successively with saturated ammonium chloride (50mL × 2), saturated aqueous common salt (50mL)
Organic layer, organic layer is dried with anhydrous magnesium sulfate, filtering, by filtrate decompression concentration to remove solvent, by residue acetic acid
Ethyl ester and petroleum ether crystallization, obtain the title compound (18.6g, yield 96%) as white solid.
ESI-MS[M]+=812.24;
13C-NMR (600MHz, CDCl3)δ:10.61,15.37,20.09,22.56,25.62,26.57,33.44,
38.36,42.69,47.43,56.30,67.96,67.98,69.87,70.05,74.31,75.61,76.36,78.71,
78.95,80.60,83.94,128.26,128.32,128.36,128.44,128.49,128.60,128.65,129.29,
130.10,131.46,133.70,135.24,135.33,145.64,154.18,154.20,166.97,170.73,201.96.
Embodiment 2
7-O- benzyloxycarbonyl groups-Baccatin III preparation
At room temperature, Baccatin III (15.0g, 25.6mmol) is dissolved in anhydrous tetrahydro furan (200mL), adds DMAP
(31.2g, 0.256mol), is heated to 40-50 DEG C.Add the anhydrous tetrahydrochysene furan containing benzyl chloroformate (43.6g, 0.256mol)
Mutter solution (100mL), monitor and react through HPLC.After completion of the reaction, filter, by filtrate decompression concentration to remove solvent, by remnants
Thing ethyl acetate (300mL) dissolves, and organic layer is washed with saturated ammonium chloride (50mL × 2), then use saturated aqueous common salt
(50mL) is washed, and is dried with anhydrous magnesium sulfate, is filtered, by filtrate decompression concentration to remove solvent, by residue ethyl acetate
With petroleum ether crystallization, the title compound (17.5g, yield 95%) as white solid is obtained.
ESI-MS[M]+=720.19.
13C-NMR (600MHz, CDCl3)δ:10.61,15.37,19.89,20.09,22.56,25.62,26.57,
33.44,38.36,42.69,47.43,56.30,67.96,69.87,70.05,74.31,75.61,76.36,78.71,
78.95,80.60,83.94,128.26,128.32,128.36,128.44,128.49,128.60,128.65,129.29,
130.10,131.46,133.70,135.24,135.33,154.18,166.97,170.21,170.73,203.59.
The preparation of the compound of formula 1
Embodiment 3
13-O- { (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7,
Benzyloxycarbonyl group -10- deacetyl baccatins the III (compound 1) of 10-O- bis- preparation.
By the benzyloxycarbonyl group -10- deacetyl baccatins III (5.6g, 6.8mmol) of 7,10-O- bis-, EDCI (2.8g,
14.6mmol), 4-N, N- lutidines (2.5g, 20.4mmol) are dissolved in toluene (100mL), are warming up under nitrogen protection
60℃.Be slowly added dropwise (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines carboxylic acid (4.1g,
10.2mmol) the solution in toluene (20mL), monitors through HPLC and reacts.After completion of the reaction, it is cooled to room temperature.By reaction solution according to
It is secondary to be washed with saturated ammonium chloride (15mL × 2), saturated sodium bicarbonate aqueous solution (20mL × 2), saturated aqueous common salt (50mL), will have
Machine layer anhydrous sodium sulfate drying, filtering, by filtrate decompression concentration to remove solvent, by residue dichloromethane-petroleum ether knot
Crystalline substance, obtains the title compound (7.3g, yield 90%) as white solid.
ESI-MS[M]+=1193.18.
Embodiment 4
13-O- { (4S, 5R) -3- benzoyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7-O-
Benzyloxycarbonyl group-Baccatin III (compound 6) preparation.
By 7-O- benzyloxycarbonyl groups-Baccatin III (3.5g, 4.85mmol), EDCI (3.7g, 19.3mmol), 4-N, N- bis-
Picoline (2.4g, 19.6mmol) is dissolved in toluene (80mL), and 60 DEG C are warming up under nitrogen protection.Be slowly added dropwise (4S,
5R) -3- benzoyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines carboxylic acids (3.9g, 9.7mmol) are at toluene (20mL)
In solution, through HPLC monitor react.After completion of the reaction, it is cooled to room temperature.By reaction solution successively with saturated ammonium chloride (15mL ×
2), saturated sodium bicarbonate aqueous solution (20mL × 2), saturated aqueous common salt (50mL) washing, with anhydrous sodium sulfate drying, are filtered, will
Filtrate decompression is concentrated to remove solvent, and residue is crystallized with dichloromethane-petroleum ether, obtained as the titled of white solid
Compound 4.9g, yield 92%.
ESI-MS[M]+=1105.38.
Using following material as raw material, according to other particular compounds of embodiment 1-4 operation preparation formula 1:
Using 10- deacetyl baccatins III as raw material, using 3- Chlorobenzyl chloroformates as protection reagent, according to embodiment 1
Operation, is made 7,10-O- bis- (3- benzyloxycarbonylchlorides base) -10- deacetyl baccatins III;Then according to the operation of embodiment 3, system
Obtain 13-O- { (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7,10-O-
Two (3- benzyloxycarbonylchlorides base) -10- deacetyl baccatins III (compound 2).
ESI-MS[M]+=1261.24.
Using 10- deacetyl baccatins III as raw material, using 4- Chlorobenzyl chloroformates as protection reagent, according to embodiment 1
Operation, is made 7,10-O- bis- (4- benzyloxycarbonylchlorides base) -10- deacetyl baccatins III;Then according to the operation of embodiment 3, system
Obtain 13-O- { (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7,10-O-
Two (4- benzyloxycarbonylchlorides base) -10- deacetyl baccatins III (compound 3).
ESI-MS[M]+=1261.18.
Using 10- deacetyl baccatins III as raw material, using allyl chlorocarbonate as protection reagent, according to the behaviour of embodiment 1
Make, the allyloxycarbonyl -10- deacetyl baccatins III of 7,10-O- bis- are made;Then according to the operation of embodiment 3,13-O- is made
The allyl oxygen of { (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7,10-O- two
Carbonyl -10- deacetyl baccatins III (compound 4).
ESI-MS[M]+=1093.56.
Using Baccatin III as raw material, using allyl chlorocarbonate as protection reagent, according to the operation of example 2, it is made with 7-O-
Allyloxycarbonyl-Baccatin III;Then according to the operation of embodiment 4,13-O- { (4S, 5R) -3- benzoyl -2- (4- are made
Methoxyphenyl) -4- phenyl -5- oxazolidines } formoxyl -7-O- allyloxycarbonyls-Baccatin III (compound 5).
ESI-MS [M] +=1055.35.
Using Baccatin III as raw material, using 3- Chlorobenzyl chloroformates as protection reagent, according to the operation of example 2,7- is made
O- (3- benzyloxycarbonylchlorides base)-Baccatin III;Then according to the operation of embodiment 4,13-O- { (4S, 5R) -3- benzoyls are made
Base -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7-O- (3- benzyloxycarbonylchlorides base)-Baccatin III (chemical combination
Thing 7).
ESI-MS[M]+=1139.46.
Using Baccatin III as raw material, using 4- Chlorobenzyl chloroformates as protection reagent, according to the operation of embodiment 2, system
Obtain 7-O- (4- benzyloxycarbonylchlorides base)-Baccatin III;Then according to the operation of embodiment 4,13-O- { (4S, 5R) -3- benzene first is made
Acyl group -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } formoxyl -7-O- (4- benzyloxycarbonylchlorides base)-Baccatin III (changes
Compound 8).
ESI-MS[M]+=1139.52.
The preparation of the compound of formula 2
Embodiment 5
The preparation of the benzyloxycarbonyl group docetaxels of 7,10-O- bis-
At room temperature, by 13-O- { (4S, 5R) -3- tertbutyloxycarbonyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines }
Benzyloxycarbonyl group -10- deacetyl baccatins the III (compound 1,5g, 4.2mmol) of formoxyl -7,10-O- bis- is dissolved in acetic acid
(20mL), adds trifluoroacetic acid (3mL), water (3mL) is slowly added dropwise.After completion of dropping, react, monitored through HPLC anti-at room temperature
Should.After completion of the reaction, continue to add water (70mL) into reaction solution, there is white solid precipitation, filter.Filter cake is washed with cold water
(30ml × 2) reduced vacuum is dried afterwards, obtains the title compound 4.2g as white solid, yield 94%.
ESI-MS[M]+=1075.51.
Embodiment 6
The benzyloxycarbonyl group docetaxel hydrochloric acid of 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] -7,10-O- two
The preparation of salt
1) preparation of (the R)-fluoro butyl chloride hydrochloride of 4-N, N- dimethylamino -2:In flask, by 4-N, N- diformazans
Base amino -2 (R)-fluoro butyrate hydrochlorate (1.67g, 9mmol) is added in thionyl chloride (10ml), is slowly heated to 40 DEG C, instead
Answer 4 hours.Thionyl chloride is removed by being evaporated under reduced pressure, anhydrous methylene chloride (25ml) is added, then it is molten by the way that removing is evaporated under reduced pressure
Agent, anhydrous methylene chloride (60ml) is added into residue, standby.
2) at -50 DEG C, the benzyloxycarbonyl group docetaxels of 7,10-O- bis- are added in anhydrous methylene chloride (150ml)
(2.2g, 2mmol), 4-N, N- lutidines (1.4g, 11.5mmol), stirring are allowed to dissolve.It is obtained in being slowly added dropwise 1)
The dichloromethane solution of 4-N, N- dimethylamino -2 (R)-fluoro butyl chloride hydrochloride, detects through HPLC and reacts.Reaction is complete
Dichloromethane layer is washed with saturated sodium-chloride water solution (with salt acid for adjusting pH to about 2.0) afterwards, it is organic with anhydrous sodium sulfate drying
Layer, filtering removes dichloromethane by rotary evaporation, and residue acetone and methyl tertiary butyl ether(MTBE) are crystallized, obtained as white
The title compound 2.16g of color solid, yield 85%.
MASS[M+H]+=1207.53.
13C-NMR(600MHz,DMSO)δ:10.83,14.62,21.52,22.88,26.57,27.27,28.56,31.13,
33.34,34.62,40.41,42.69,43.26,46.65,52.34,55.34,55.84,69.83,69.93,71.73,
74.31,75.56,75.99,77.05,78.32,79.14,80.13,83.17,85.84,87.05,127.83,128.8,
128.84,128.96,129.02,129.16,130.07,130.12,132.66,134.06,135.53,135.63,137.50,
141.78,153.88,153.93,155.66,165.65,169.05,170.5,202.1。
Embodiment 7
The preparation of 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] docetaxel hydrochloride
At room temperature, it is 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] bis- benzyloxycarbonyl groups of -7,10-O- are more
Xi Tasai hydrochlorides (1.25g, 1mmol) are dissolved in anhydrous tetrahydro furan (30ml), add 10%Pd/C (120mg).Put with nitrogen
Take a breath after body, be passed through hydrogen, react 1.5 hours at room temperature.After reaction completely, with anhydrous tetrahydro furan (20ml) diluting reaction
Liquid, filtering, by filter cake by the removing solvent that is concentrated under reduced pressure, obtains the title compound 0.88g as white solid, yield
90%.
ESI-MS[M+H]+=939.37.
13C-NMR(600MHz,DMSO)δ:209.458,169.376,168.425,167.682,167.513,166.869,
165.229,155.167,137.026,136.896,135.884,133.171,131.278,129.960,129.539,
128.542,128.044,127.201,86.406,85.187,83.701,80.367,79.033,78.811,78.596,
76.788,75.416,74.703,73.715,71.883,70.710,67.308,57.007,54.708,51.949,45.925,
42.867,42.515,42.086,39.909,39.771,39.625,39.488,39.350,39.212,39.074,38.077,
36.391,34.675,29.777,28.980,28.337,28.061,26.566,26.436,26.298,23.209,22.405,
20.627,13.806,13.614,10.717,9.667。
Embodiment 8
The preparation of 7-O- benzyloxycarbonyl group taxols
At room temperature, by 13-O- { (4S, 5R) -3- benzoyls -2- (4- methoxyphenyls) -4- phenyl -5- oxazolidines } first
Acyl group -7-O- benzyloxycarbonyl groups-Baccatin III (compound 6,4g, 3.6mmol) are dissolved in acetic acid (22mL), add trifluoroacetic acid
(5mL), is slowly added dropwise water (3ml).After completion of dropping, monitor and react through HPLC.After completion of the reaction, water is added into reaction
(50mL), there is white solid precipitation, filtering, and filter cake is washed after (25ml × 2) with cold water, and reduced vacuum is dried, and obtains conduct
The title compound 3.4g of white solid, yield 95%.
ESI-MS[M]+=987.34.
13C-NMR(600MHz,CDCl3)δ:203.64,171.32,170.65,168.96,165.98,165.86,
154.21,140.36,140.21,137.12,134.65,134.12,133.98,133.89,133.21,130.65,129.94,
128.98,128.54,128.43,128.12,85.12,81.45,78.23,76.58,76.46,76.45,74.98,72.56,
70.23,68.13,59.64,53.03,48.65,43.45,42.26,41.96,38.96,34.45,28.20,21.65,
21.01,11.23.
Embodiment 9
The system of 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] -7-O- benzyloxycarbonyl group Japanese yew alcohol hydrochlorides
It is standby
1) preparation of (the R)-fluoro butyl chloride hydrochloride of 4-N, N- dimethylamino -2:In flask, by 4-N, N- diformazans
Base amino -2 (R)-fluoro butyrate hydrochlorate (1.67g, 9mmol) is added in thionyl chloride (10ml), is slowly heated to 40 DEG C, instead
Answer 4 hours.Thionyl chloride is removed by being evaporated under reduced pressure, anhydrous methylene chloride (25ml) is added, then it is molten by the way that removing is evaporated under reduced pressure
Agent, anhydrous methylene chloride (60ml) is added into residue, standby.
2) at -50 DEG C, add in the anhydrous methylene chloride (150ml) 7-O- benzyloxycarbonyl groups taxol (2.2g,
2.2mmol), 4-N, N- lutidines (1.4g, 11.5mmol), stirring are allowed to dissolve.Obtained 4-N in being slowly added dropwise 1),
The dichloromethane solution of N- dimethylaminos -2 (R)-fluoro butyl chloride hydrochloride, detects through HPLC and reacts.Used after reaction completely
Saturated sodium-chloride water solution (with salt acid for adjusting pH to about 2.0) washs dichloromethane layer, uses anhydrous sodium sulfate drying organic layer, mistake
Filter, dichloromethane is removed by rotary evaporation, and residue acetone and methyl tertiary butyl ether(MTBE) are crystallized, obtained as white solid
Title compound 2.05g, yield 80%.
MASS[M+H]+=1119.41.
13C-NMR(600MHz,DMSO)δ:203.64,171.32,170.65,169.63,168.96,165.98,
165.86,154.21,140.36,140.21,137.12,134.65,134.12,133.98,133.89,133.21,130.65,
129.94,128.98,128.54,128.43,128.12,85.12,81.45,80.65,78.23,76.58,76.46,76.45,
74.98,72.56,70.23,68.27,59.64,54.87,53.03,48.65,43.45,42.26,42.15,41.96,
38.96,34.45,28.20,23.97,21.65,21.01,11.23。
Embodiment 10
The preparation of 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] Japanese yew alcohol hydrochloride
At room temperature, by 2 '-O- [4-N, N- dimethylamino -2 (R)-fluoro bytyry] -7-O- benzyloxycarbonyl group Japanese yew alkoxide
Hydrochlorate (1.30g, 1.1mmol) is dissolved in anhydrous tetrahydro furan (30ml), adds 10%Pd/C (130mg).Use nitrogen displacement gas
After body, hydrogen is passed through, is stirred at room temperature.After reaction completely, with anhydrous tetrahydro furan (20ml) dilute reaction solution, filter, will
Filter cake obtains the title compound 1.05g as white solid, yield 91% by the removing solvent that is concentrated under reduced pressure.
ESI-MS[M+H]+=985.37.
13C-NMR(600MHz,DMSO)δ:203.64,171.32,170.65,169.63,168.96,165.98,
165.86,140.36,140.21,137.12,134.65,134.12,133.98,133.89,133.21,130.65,129.94,
128.98,128.54,128.43,128.12,85.12,81.45,80.65,78.23,76.58,76.46,76.45,74.98,
72.56,70.23,59.64,54.87,53.03,48.65,43.45,42.26,42.15,41.96,38.96,34.45,
28.20,23.97,21.65,21.01,11.23。
Claims (6)
1. the method for the compound of formula 2:
Wherein:
R1For tert-butoxy or phenyl;
R2For H or acetyl group;
X is H, C1-6Alkyl or F;
Y is F or the C replaced by one or more F1-6Alkyl;
N is 1,2,3,4,5 or 6;
W is NR5R6A or
R5、R6The C for be each independently H, being optionally substituted by phenyl1-6Alkyl or C3-6Cycloalkyl;
M is 0,1,2 or 3;And
A is pharmaceutically acceptable acid,
It is characterized in that:The compound of the formula 2 is prepared by raw material of the compound of formula 1:
Wherein:
R1As the compound to formula 2 is defined;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens, preferably acetyl group,
The benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more chlorine, more preferably acetyl group, benzyloxycarbonyl group, 3- chlorine
Benzyloxycarbonyl group, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens, be preferably optionally by one or
The benzyloxycarbonyl group or allyloxycarbonyl of multiple chlorine substitutions, more preferably benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchloride bases
Or allyloxycarbonyl.
2. the method as described in claim 1, it is characterised in that:Work as R2During for H, R3Optionally to be taken by one or more halogens
The benzyloxycarbonyl group or allyloxycarbonyl in generation, are preferably the benzyloxycarbonyl group or allyl oxygen carbonyl optionally replaced by one or more chlorine
Base, more preferably benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl;Work as R2During for acetyl group, R3For
Acetyl group.
3. method as claimed in claim 1 or 2, it is characterised in that:By raw material of the compound of the formula 1 via following reaction
Route 1 prepares the compound of the formula 2:
Reaction scheme 1
Wherein R1、R2、R3、R4, W, X, Y and n it is as defined in claim 1;And;
G is halogen or hydroxyl, preferably chlorine, bromine or hydroxyl.
4. the compound of formula 1, its pharmaceutically acceptable salt, polymorph or solvate:
Wherein,
R1For tert-butoxy or phenyl;
R3The benzyloxycarbonyl group or allyloxycarbonyl for acetyl group, optionally replaced by one or more halogens, preferably acetyl group,
The benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more chlorine, more preferably acetyl group, benzyloxycarbonyl group, 3- chlorine
Benzyloxycarbonyl group, 4- benzyloxycarbonylchlorides base or allyloxycarbonyl;And
R4For the benzyloxycarbonyl group or allyloxycarbonyl optionally replaced by one or more halogens, be preferably optionally by one or
The benzyloxycarbonyl group or allyloxycarbonyl of multiple chlorine substitutions, more preferably benzyloxycarbonyl group, 3- benzyloxycarbonylchlorides base, 4- benzyloxycarbonylchloride bases
Or allyloxycarbonyl.
5. compound as claimed in claim 4, its pharmaceutically acceptable salt, polymorph or solvate, the compound
It is selected from:
6. prepare the method for compound as claimed in claim 4, it is characterised in that:Prepared via following reaction scheme 2 described
The compound of formula 1:
Reaction scheme 2
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510884378 | 2015-12-04 | ||
CN2015108843787 | 2015-12-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107056767A true CN107056767A (en) | 2017-08-18 |
CN107056767B CN107056767B (en) | 2022-07-15 |
Family
ID=59619534
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201611101895.3A Active CN107056767B (en) | 2015-12-04 | 2016-12-05 | Process and intermediates for the preparation of water-soluble taxane derivatives |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN107056767B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111718309A (en) * | 2019-03-19 | 2020-09-29 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1143641A (en) * | 1995-03-22 | 1997-02-26 | 布里斯托尔-迈尔斯斯奎布公司 | Novel methods for preparation of taxanes using oxazolidine intermediates |
CN1262683A (en) * | 1997-06-20 | 2000-08-09 | 巴克·诺顿药物有限公司 | Soluble prodrugs of paclitaxel |
CN1502614A (en) * | 1999-03-02 | 2004-06-09 | Intermediate for priparing taxanes derivative | |
JP2005029543A (en) * | 2003-07-11 | 2005-02-03 | Yoshiaki Kiso | Water-soluble prodrug |
CN1681799A (en) * | 2002-09-10 | 2005-10-12 | 因德纳有限公司 | Taxane derivatives functionalized at the 14- position and a process for the preparation thereof |
CN101007795A (en) * | 2007-01-26 | 2007-08-01 | 浙江大学 | Paclitaxel and docetaxel synthesis method |
WO2012088422A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
CN104650109A (en) * | 2013-11-22 | 2015-05-27 | 天士力控股集团有限公司 | Taxane compound |
WO2015120822A1 (en) * | 2014-02-17 | 2015-08-20 | 江苏恩华络康药物研发有限公司 | Water-soluble taxane derivatives and uses thereof |
-
2016
- 2016-12-05 CN CN201611101895.3A patent/CN107056767B/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1143641A (en) * | 1995-03-22 | 1997-02-26 | 布里斯托尔-迈尔斯斯奎布公司 | Novel methods for preparation of taxanes using oxazolidine intermediates |
CN1262683A (en) * | 1997-06-20 | 2000-08-09 | 巴克·诺顿药物有限公司 | Soluble prodrugs of paclitaxel |
CN1502614A (en) * | 1999-03-02 | 2004-06-09 | Intermediate for priparing taxanes derivative | |
CN1681799A (en) * | 2002-09-10 | 2005-10-12 | 因德纳有限公司 | Taxane derivatives functionalized at the 14- position and a process for the preparation thereof |
JP2005029543A (en) * | 2003-07-11 | 2005-02-03 | Yoshiaki Kiso | Water-soluble prodrug |
CN101007795A (en) * | 2007-01-26 | 2007-08-01 | 浙江大学 | Paclitaxel and docetaxel synthesis method |
WO2012088422A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
CN104650109A (en) * | 2013-11-22 | 2015-05-27 | 天士力控股集团有限公司 | Taxane compound |
WO2015120822A1 (en) * | 2014-02-17 | 2015-08-20 | 江苏恩华络康药物研发有限公司 | Water-soluble taxane derivatives and uses thereof |
Non-Patent Citations (5)
Title |
---|
MARIUSZ SKWARCZYNSKI, ET AL.: ""No Auxiliary, No Byproduct Strategy for Water-Soluble Prodrugs of Taxoids: Scope and Limitation of O-N Intramolecular Acyl and Acyloxy Migration Reactions"", 《J. MED. CHEM.》 * |
张军良,郭燕文主编: "《有机合成设计原理与应用》", 31 May 2005, 中国医药科技出版社 * |
田睿: "紫杉烷类水溶性衍生物的制备及初步生物活性研究", 《中国博士学位论文全文数据库》 * |
蒲俊勇: "紫杉烷类水溶性前药的设计与合成", 《中国优秀硕士学位论文全文数据库》 * |
赵临襄 主编: "《化学制药工艺学 第4版》", 31 August 2015, 中国医药科技出版社出版 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111718309A (en) * | 2019-03-19 | 2020-09-29 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
CN111718309B (en) * | 2019-03-19 | 2022-08-02 | 上海茂晟康慧科技有限公司 | Synthesis method of paclitaxel side chain and analogues thereof |
Also Published As
Publication number | Publication date |
---|---|
CN107056767B (en) | 2022-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4104463B2 (en) | Process for preparing 4 "-substituted-9-deoxo-9A-aza-9A-homoerythromycin derivatives | |
WO2008038965A1 (en) | 7alpha-aminosteroid derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and composition for anticancer or antibiotics containing the same as an active ingredient | |
JP2010506932A (en) | Method for producing crystalline anhydrous docetaxel | |
CN113087712B (en) | L-amino acid-6-gliotoxin ester trifluoroacetate and preparation method thereof | |
JP2008519787A (en) | Macrolone compounds | |
US10870654B2 (en) | Pharmaceutically acceptable salts and polymorphic forms of hydrocodone benzoic acid enol ester and processes for making same | |
CA3113463A1 (en) | Nitroxoline prodrug and use thereof | |
CN104736539B (en) | Sepiapterin and the autofrettage of tetrahydrochysene lactoyl pterin | |
EP2594552A2 (en) | Method for preparing ramalin | |
CN102471273B (en) | 2-[[[2-[(hydroxyacetyl)amino]-4-pyridinyl]methyl]thio]-n-[4-(trifluoromethoxy)phenyl]-3-pyridinecarboxamide benzene- sulfonate, crystals of same, polymorphs thereof, and processes for production thereof | |
CN107056767A (en) | Method and intermediate for preparing water-soluble taxane analog derivative | |
KR101595747B1 (en) | Method for preparing of nafamostat mesilate | |
JP6275644B2 (en) | N- [2-({2-[(2S) -2-cyanopyrrolidin-1-yl] -2-oxoethyl} amino) -2-methylpropyl] -2-methylpyrazolo [1,5-a] pyrimidine-6 -Carboxamide crystals | |
EP3360858B1 (en) | Process for producing an aminopyrrolidine derivative | |
WO2015111085A2 (en) | Processes for the preparation of eltrombopag and pharmaceutically acceptable salts, solvates and intermediates thereof | |
KR20180052728A (en) | Process for the preparation of indolin compounds and novel indolin salts | |
CN103922986B (en) | Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application | |
CN104817482B (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
JPS6219438B2 (en) | ||
CN107922329B (en) | Process and intermediates for the preparation of water-soluble taxane derivatives | |
CN104059087B (en) | A kind of synthetic method of aspoxicillin | |
KR100367981B1 (en) | Process for preparing form ii crystals of clarithromycin and crystalline clarithromycin mesilate trihydrate used therein | |
JP2906663B2 (en) | 5-0-desosaminylerythronolide A derivative | |
JP2002255932A (en) | Method for producing 3-alkylaminoazetidine | |
AU2020261218A1 (en) | Cytidine derivatives and methods of forming cytidine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |