CN107056767B - Process and intermediates for the preparation of water-soluble taxane derivatives - Google Patents
Process and intermediates for the preparation of water-soluble taxane derivatives Download PDFInfo
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Abstract
The invention discloses a method for preparing taxane derivatives shown in a formula 2, a compound shown in a formula 1 and a preparation method thereof, wherein the compound is used as a raw material or an intermediate for preparing the taxane derivatives shown in the formula 2.
Description
Cross Reference to Related Applications
This application claims priority to chinese patent application No. 201510884378.7 filed on day 4, 12/2015, the disclosure of which is incorporated herein by reference.
Technical Field
The invention belongs to the field of medicines, and relates to a method and an intermediate for preparing water-soluble taxane derivatives and a method for preparing the intermediate.
Background
Taxane medicines (such as paclitaxel and docetaxel) are excellent antitumor medicines, are mainly used for treating advanced breast cancer, ovarian cancer, non-small cell lung cancer, prostate cancer and the like, and also have certain curative effects on head and neck cancer, gastric cancer, pancreatic cancer, melanoma and the like. However, although the anticancer activity of taxanes is good, they have poor water solubility and low bioavailability when orally administered, and thus can be clinically administered only by injection. When the compound is clinically used, nonionic surfactants such as polyethoxylated castor oil or tween-80 and the like are usually added for dissolving to prepare injection. Unfortunately, these surfactants have side effects such as vasodilation, blood pressure reduction, hepatotoxicity and severe allergic reactions, which have limited the clinical use of taxanes. In view of this, many pharmacologists in the world seek to change this state by structural modifications.
In international patent application No. PCT/CN2015/073178, filed by the applicant of the present invention on month 2 in 2015, a water-soluble taxane prodrug having the structure of the following formula 2 is reported. The prodrug has good water solubility and anti-tumor activity consistent with that of a raw drug, so that the toxic and side effects caused by a cosolvent in the original taxane injection are eliminated:
wherein R is1Is tert-butoxy or phenyl; r is2Is H or acetyl; x is H, C1-6Alkyl or F; y being F or C substituted by one or more F1-6An alkyl group; n is 1, 2, 3, 4, 5 or 6; w is NR5R6A or
R5、R6Each independently of the other is H, optionally substituted by benzeneRadical substituted C1-6Alkyl, or C3-6A cycloalkyl group; m is 0, 1, 2 or 3; a is a pharmaceutically acceptable acid.
In the above-mentioned patent application, the following two methods for preparing the compound of formula 2 are described:
firstly, docetaxel or paclitaxel is used as a raw material and reacts with amino acid chloride under the catalysis of triethylamine, pyridine or DMAP, so as to prepare a compound shown in a formula 2;
secondly, docetaxel or paclitaxel is used as a raw material, and organic base such as DMAP, triethylamine or pyridine is used as a catalyst to react with amino acid in the presence of a compound with a carbodiimide structure (such as DCC, EDCI and the like), so as to prepare the compound of the formula 2.
Although both methods can produce the compound of formula 2, since the structures of docetaxel and paclitaxel have hydroxyl groups at 7-position and/or 10-position in addition to hydroxyl group at 2 ' -position, 7-position and/or 10-position substituted products and 2 ' -position and 7-position and/or 2 ' -position and 10-position simultaneously substituted disubstituted products, even more substituted products, are generated during the preparation process, so that not only the yield of the final product is reduced, but also a large amount of impurities affecting the product quality are generated.
Disclosure of Invention
According to a first aspect of the present invention, there is provided a process for preparing a taxane derivative represented by formula 2:
wherein:
R1is tert-butoxy or phenyl;
R2is H or acetyl;
x is H, C1-6Alkyl or F;
y being F or C substituted by one or more F1-6An alkyl group;
n is 1, 2, 3, 4, 5 or 6;
w is NR5R6A or
R5、R6Each independently H, C optionally substituted by phenyl1-6Alkyl, or C3-6A cycloalkyl group;
m is 0, 1, 2 or 3; and is
A is a pharmaceutically acceptable acid, and the acid,
the method comprises the following steps: preparing the compound of formula 2 from a compound of formula 1:
wherein:
R1as defined hereinbefore for the compound of formula 2;
R3is acetyl, benzyloxycarbonyl optionally substituted with one or more halogens, or allyloxycarbonyl; and is
R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one or more halogens.
Compared with the two methods disclosed in international patent application No. PCT/CN2015/073178, the method provided by the invention produces little (even no) impurity caused by 7-position substitution and/or 10-position substitution and disubstituted impurity caused by simultaneous substitution of 2 'position and 7 position and/or by simultaneous substitution of 2' position and 10 position, has higher yield and product purity, and mild reaction conditions, and the final product (i.e. the compound of formula 2) is easier to separate.
According to a second aspect of the present invention, there is provided an intermediate compound for preparing a compound of formula 2, having the following general formula 1:
wherein, the first and the second end of the pipe are connected with each other,
R1is tert-butoxy or phenyl;
R3is acetyl, benzyloxycarbonyl optionally substituted with one or more halogens, or allyloxycarbonyl; and is
R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one or more halogens.
According to a third aspect of the present invention, there is provided a process for the preparation of an intermediate compound of formula 1 as described above, which process comprises: the compounds of formula 1 are prepared via the following reaction scheme 2:
reaction scheme 2
Detailed Description
Definition of
The term "halogen" as used herein means fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The term "C" as used herein1-6Alkyl "means a saturated straight-chain or branched-chain hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, more preferably methyl, ethyl, propyl or isopropyl.
The term "C" as used herein3-6Cycloalkyl "means a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The term "benzyloxycarbonyl" as used herein refers to a benzyloxy group attached to the rest of the molecule by a carbonyl bond.
The term "allyloxycarbonyl" as used herein refers to an allyloxy group attached to the remainder of the molecule through a carbonyl bond.
The term "pharmaceutically acceptable acid" as used herein refers to pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, acetic acid, propionic acid, methanesulfonic acid, lactic acid, benzenesulfonic acid, p-toluenesulfonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid or malic acid.
The compounds of the present invention may exist in the form of their pharmaceutically acceptable salts, including their acid and base addition salts.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogenphosphate, pyroglutamate, saccharate, dihydrogenphosphate, pyroglutamate, dihydrogensulfate, dihydrogenphosphate, dihydrogensulfate, borate, dihydrogenphosphate, dihydrogensulfate, gluconate, and the like, Stearates, succinates, tannates, tartrates, tosylates, trifluoroacetates, xinafoates, and the like.
Suitable base addition salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, zinc salts, and the like.
The compounds of the invention may exist in their crystalline or polymorphic forms, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
The compounds of the invention may exist in the form of their solvates, in particular hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as water, ethanol, isopropanol, ethyl acetate or acetone. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Preparing a compound of formula 2 from a compound of formula 1
An object of the present invention is to provide a process for preparing a taxane derivative represented by formula 2:
wherein:
R1is tert-butoxy or phenyl;
R2is H or acetyl;
x is H, C1-6Alkyl or F;
y is F or C substituted by one or more F1-6An alkyl group;
n is 1, 2, 3, 4, 5 or 6;
w is NR5R6A or
R5、R6Each independently of the other being H, C optionally substituted by phenyl1-6Alkyl, or C3-6A cycloalkyl group;
m is 0, 1, 2 or 3; and is provided with
A is a pharmaceutically acceptable acid, and A is a pharmaceutically acceptable acid,
the method comprises the following steps: preparing the compound of formula 2 from a compound of formula 1:
wherein:
R1as hereinbefore defined for the compound of formula 2;
R3is acetyl, benzyloxycarbonyl optionally substituted with one or more halogens, or allyloxycarbonyl; and is
R4Is optionally selected fromBenzyloxycarbonyl substituted with one or more halogens, or allyloxycarbonyl.
According to one embodiment of the invention, X is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or F.
According to one embodiment of the invention Y is F or methyl, ethyl, propyl, isopropyl, butyl or isobutyl substituted by one or more F. Preferably, Y is F, CF3、CH2F or CHF2。
According to one embodiment of the invention, R5、R6Each independently H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
According to one embodiment of the invention, R3Is acetyl, benzyloxycarbonyl optionally substituted with one or more chlorines, or allyloxycarbonyl. Preferably, R3Acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
According to one embodiment of the invention, when R2When is H, R3Is benzyloxycarbonyl optionally substituted by one or more halogens, or allyloxycarbonyl, preferably benzyloxycarbonyl optionally substituted by one or more chlorines, or allyloxycarbonyl, more preferably benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, or allyloxycarbonyl; when R is2When it is acetyl, R3Is acetyl.
According to one embodiment of the invention, R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one or more chlorine. Preferably, R4Is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
According to one embodiment of the invention, the method comprises: the compound of formula 2 is prepared from the compound of formula 1 via the following reaction scheme 1:
reaction scheme 1
Wherein R is1、R2、R3、R4W, X, Y and n are as defined above; and;
g is halogen or hydroxy.
According to one embodiment of the invention, G is chloro, bromo or hydroxy.
And 3, step 3:
step 3 comprises removing the protecting group at the 2' -position from the compound of formula 1, thereby obtaining the compound of formula 3.
Preferably, the reaction of step 3 is carried out under acidic conditions.
According to one embodiment of the invention, step 3 comprises:
the compound of formula 1 is deprotected at the 2' position in a suitable solvent at a suitable temperature in the presence of an acidic reagent to give a compound of formula 3.
Preferably, the temperature is from 0 to 60 ℃, preferably from 20 to 35 ℃.
Preferably, the solvent is water, methanol, ethanol, tetrahydrofuran, acetic acid, or a combination thereof, more preferably acetic acid or tetrahydrofuran.
Preferably, the acidic reagent is acetic acid or trifluoroacetic acid, more preferably trifluoroacetic acid.
And 4, step 4:
step 4 comprises reacting the compound of formula 3 with the compound of formula 8 to obtain the compound of formula 9.
According to one embodiment of the present invention, the reaction of step 4 is carried out in the presence of a nitrogen-containing basic organic reagent or a mixed reagent composed of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure.
Preferably, the nitrogen-containing basic organic reagent is an organic base such as triethylamine, pyridine, DMAP, 4-PPY, or a combination thereof.
Preferably, the compound having a carbodiimide structure is DCC, EDCI, or a combination thereof.
Preferably, in the mixed reagent composed of the nitrogen-containing basic organic reagent and the compound having a carbodiimide structure, the molar ratio of the former to the latter is 1: (1-5).
According to one embodiment of the invention, when G in the compound of formula 8 is halogen (e.g. chlorine or bromine), step 4 is carried out in the presence of a nitrogen-containing basic organic reagent.
According to one embodiment of the present invention, when G in the compound of formula 8 is halogen (e.g., chloro or bromo), step 4 comprises:
reacting a compound of formula 3 with a compound of formula 8 in an organic solvent in the presence of a nitrogen-containing basic organic reagent at an appropriate temperature to produce a compound of formula 9.
Preferably, the temperature is-100-40 ℃, preferably-60-0 ℃, more preferably-30-0 ℃.
Preferably, the molar ratio of the compound of formula 3, the compound of formula 8 and the 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-dichloroethane, or a combination thereof.
According to one embodiment of the present invention, when G in the compound of formula 8 is a hydroxyl group, step 4 is performed in the presence of a mixed reagent composed of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure.
According to an embodiment of the present invention, when G in the compound of formula 8 is hydroxy, step 4 comprises:
the compound of formula 3 is reacted with the compound of formula 8 in an organic solvent in the presence of a mixed reagent of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure at an appropriate temperature, thereby preparing the compound of formula 9.
Preferably, the temperature is from-60 to 40 ℃, preferably from 0 to 30 ℃, more preferably from 5 to 25 ℃.
Preferably, the molar ratio of the compound of formula 3, the compound of formula 8 and the mixed reagent of the nitrogen-containing basic organic reagent and the compound having a carbodiimide structure is 1: 1-12.0: 1-15.0, preferably 1: 1-4.0: 1-8.0, wherein the molar amount of the mixed reagent is based on the nitrogen-containing basic organic reagent.
Preferably, the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, or a combination thereof.
And 5:
step 5 comprises hydrogenolysis of the compound of formula 9 to provide the compound of formula 2.
Preferably, the hydrogenolysis is carried out in the presence of a Pd reagent.
According to one embodiment of the invention, step 5 comprises:
adding a Pd reagent into an organic solvent containing the compound of the formula 9 at a proper temperature, introducing hydrogen into the reaction solution, and obtaining the compound of the formula 2 after the reaction is finished.
Preferably, the temperature is-30-50 ℃, preferably 10-35 ℃.
Preferably, the organic solvent is tetrahydrofuran, 1, 4-dioxane, ethyl acetate, butyl acetate, or a combination thereof.
Preferably, the Pd reagent is Pd/C, PdCl2、Pd(PPh3)4Or a combination thereof, more preferably Pd/C containing Pd in an amount of 5-30%, most preferably Pd/C containing Pd in an amount of 5-10%.
Preferably, the amount of the Pd reagent is 5-60%, preferably 10-30% of the amount of the compound of formula 9.
Preferably, the pressure of the hydrogen gas introduced is 1 to 5atm, preferably 1 to 2 atm.
The process of the present invention overcomes the disadvantages of the prior routes that result in impurities resulting from 7-and/or 10-position substitution, disubstituted impurities resulting from simultaneous substitution of the 2 'and 7 positions and/or from simultaneous substitution of the 2' and 10 positions, and even more substituted impurities. The compound of formula 2 prepared by the method has higher yield and product purity, and the method has mild reaction conditions and easier separation of final products.
Intermediate compound
Another object of the present invention is to provide an intermediate compound, a pharmaceutically acceptable salt, polymorph or solvate thereof, for preparing the compound of formula 2, said intermediate compound having the following general formula 1:
wherein, the first and the second end of the pipe are connected with each other,
R1is tert-butoxy or phenyl;
R3is acetyl, benzyloxycarbonyl optionally substituted with one or more halogens, or allyloxycarbonyl; and is
R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one or more halogens.
According to one embodiment of the invention, R3Is acetyl, benzyloxycarbonyl optionally substituted with one or more chloro, or allyloxycarbonyl. Preferably, R3Is acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
According to one embodiment of the invention, R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one or more chlorine. Preferably, R4Is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
According to one embodiment of the invention, the compound of formula 1 of the invention is selected from:
the compound of formula 1 can be used as a raw material or a reaction intermediate for preparing the water-soluble taxane derivative of formula 2, can be used as a reference for monitoring the reaction process for preparing the compound of formula 2, and can be used as an impurity reference for detecting a bulk drug or a pharmaceutical preparation containing the compound of formula 2.
Preparation of intermediate compounds
It is still another object of the present invention to provide a method for preparing the intermediate compound of formula 1 above. The method comprises the following steps: compounds of formula 1 are prepared via the following reaction scheme 2:
reaction scheme 2
Wherein R is1、R2、R3And R4As defined hereinbefore.
Step 1:
step 1 comprises acylating the compound of formula 5 with an acylating agent to protect the hydroxyl group at position 7 and/or position 10 of the compound of formula 5 to obtain the compound of formula 6.
According to one embodiment of the invention, the acylating agent is benzyl chloroformate, 3-chlorobenzyl chloroformate, 4-chlorobenzyl chloroformate or allyl chloroformate.
According to one embodiment of the present invention, reference may be made to patent No. US6307071 or xu hou, docetaxel synthesis process, technical bulletin 2010(28) 13: the method reported in 82-86 proceeds to the reaction of step 1.
And 2, step:
step 2 comprises subjecting the compound of formula 6 to a condensation reaction with the compound of formula 7, thereby obtaining the compound of formula 1.
Preferably, the reaction of step 2 is carried out under basic conditions.
According to one embodiment of the invention, step 2 comprises:
reacting the compound of formula 6 with the compound of formula 7 in the presence of a nitrogen-containing basic organic reagent and a compound having a carbodiimide structure in an organic solvent at an appropriate temperature to prepare the compound of formula 1.
Preferably, the temperature is from 30 to 80 ℃, more preferably from 40 to 60 ℃.
Preferably, the nitrogen-containing basic organic reagent is an organic base such as triethylamine, pyridine, DMAP, 4-PPY, or a combination thereof.
Preferably, the compound having a carbodiimide structure is DCC, EDCI, or a combination thereof.
Preferably, the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, toluene, or a combination thereof.
According to one embodiment of the present invention, the reaction of step 2 can be carried out with reference to the method reported in patent No. US 20040073044.
The method for preparing the compound shown in the formula 1 has the advantages of simple process and mild reaction conditions, and is suitable for industrial production.
Examples
In order to make the objects and technical solutions of the present invention more apparent, preferred embodiments of the present invention are described in detail below. It is to be noted that: the following examples are intended to illustrate the invention further and are not to be construed as limiting the scope of the invention. The invention is not limited to the specific embodiments described above, but rather only to the specific embodiments described above. Further, specific experimental methods not mentioned in the following examples were carried out according to the usual experimental methods.
The abbreviations herein have the following meanings:
| DMAP | 4-N, N-dimethylaminopyridine |
| DCC | Dicyclohexylcarbodiimide |
| EDCI | 1-Ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride |
| 4-PPY | 4-pyrrolidinylpyridines |
Preparation of the Compound of formula 6
Example 1
Preparation of 7, 10-O-dibenzyloxycarbonyl-10-deacetylbaccatin III
10-deacetylbaccatin III (13.0g, 23.9mmol) was dissolved in anhydrous tetrahydrofuran (180mL) at room temperature, DMAP (29.1g, 0.239mol) was added and the mixture was heated to 40-50 ℃. A solution of benzyl chloroformate (40.7g, 0.239mol) in dry tetrahydrofuran (80mL) was added and the reaction was monitored by HPLC. After completion of the reaction, filtration was performed, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was dissolved in ethyl acetate (300mL), the organic layer was washed successively with saturated ammonium chloride (50mL × 2) and saturated brine (50mL), the organic layer was dried over anhydrous magnesium sulfate, filtration was performed, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was crystallized from ethyl acetate and petroleum ether to obtain the title compound (18.6g, yield 96%) as a 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。
Example 2
Preparation of 7-O-benzyloxycarbonyl-baccatin III
Baccatin III (15.0g, 25.6mmol) was dissolved in anhydrous tetrahydrofuran (200mL) at room temperature, DMAP (31.2g, 0.256mol) was added and heated to 40-50 ℃. A solution of benzyl chloroformate (43.6g, 0.256mol) in dry tetrahydrofuran (100mL) was added and the reaction was monitored by HPLC. After completion of the reaction, filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was dissolved in ethyl acetate (300mL), the organic layer was washed with saturated ammonium chloride (50mL × 2) and then with saturated brine (50mL), dried over anhydrous magnesium sulfate, filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was crystallized from ethyl acetate and petroleum ether to obtain the title compound (17.5g, yield 95%) as a white solid.
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。
Preparation of the Compound of formula 1
Example 3
Preparation of 13-O- { (4S, 5R) -3-tert-Butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7, 10-O-dibenzyloxycarbonyl-10-deacetylbaccatin III (Compound 1).
7, 10-O-dibenzyloxycarbonyl-10-deacetylbaccatin III (5.6g, 6.8mmol), EDCI (2.8 g, 14.6mmol), 4-N, N-lutidine (2.5g, 20.4mmol) were dissolved in toluene (100mL) and the temperature was raised to 60 ℃ under nitrogen. A solution of (4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidinecarboxylic acid (4.1g, 10.2mmol) in toluene (20mL) was slowly added dropwise and the reaction monitored by HPLC. After the reaction was completed, it was cooled to room temperature. The reaction solution was washed with saturated ammonium chloride (15mL × 2), saturated aqueous sodium bicarbonate (20mL × 2), and saturated brine (50mL) in this order, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was crystallized from dichloromethane-petroleum ether to give the title compound (7.3g, yield 90%) as a white solid.
ESI-MS[M]+＝1193.18。
Example 4
Preparation of 13-O- { (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7-O-benzyloxycarbonyl-baccatin III (Compound 6).
7-O-benzyloxycarbonyl-baccatin III (3.5g, 4.85mmol), EDCI (3.7g, 19.3 mmol), 4-N, N-lutidine (2.4g, 19.6mmol) were dissolved in toluene (80mL) and the temperature was raised to 60 ℃ under nitrogen. A solution of (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidinecarboxylic acid (3.9g, 9.7mmol) in toluene (20mL) was slowly added dropwise and the reaction monitored by HPLC. After the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was washed successively with saturated ammonium chloride (15mL × 2), saturated aqueous sodium bicarbonate (20mL × 2), and saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was crystallized from dichloromethane-petroleum ether to give 4.9g of the title compound as a white solid in 92% yield.
ESI-MS[M]+＝1105.38。
Other specific compounds of formula 1 were prepared following the procedures of examples 1-4 starting from the following materials:
by using 10-deacetylbaccatin III as a raw material and 3-chlorobenzyl chloroformate as a protective reagent, 7, 10-O-bis (3-chlorobenzyloxycarbonyl) -10-deacetylbaccatin III was prepared by the procedure of example 1; then, by following the procedure of example 3, 13-O- { (4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7, 10-O-bis (3-chlorobenzyloxycarbonyl) -10-deacetylbaccatin III (Compound 2) was obtained.
ESI-MS[M]+＝1261.24。
By using 10-deacetylbaccatin III as a raw material and 4-chlorobenzyl chloroformate as a protective reagent, 7, 10-O-bis (4-chlorobenzyloxycarbonyl) -10-deacetylbaccatin III was prepared by the procedure of example 1; then, by following the procedure of example 3, 13-O- { (4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7, 10-O-bis (4-chlorobenzyloxycarbonyl) -10-deacetylbaccatin III (Compound 3) was obtained.
ESI-MS[M]+＝1261.18。
Preparing 7, 10-O-diallyloxycarbonyl-10-deacetylbaccatin III from 10-deacetylbaccatin III as a raw material and allyl chloroformate as a protective reagent according to the operation of example 1; then, by following the procedure of example 3, 13-O- { (4S, 5R) -3-t-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7, 10-O-diallyloxycarbonyl-10-deacetylbaccatin III (compound 4) was obtained.
ESI-MS[M]+＝1093.56。
Preparing 7-O-allyloxycarbonyl-baccatin III by taking baccatin III as a raw material and allyl chloroformate as a protective reagent according to the operation of example 2; then, by following the procedure of example 4, 13-O- { (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7-O-allyloxycarbonyl-baccatin III (compound 5) was obtained.
ESI-MS[M]+＝1055.35。
Preparing 7-O- (3-chlorobenzyloxycarbonyl) -baccatin III by using baccatin III as a raw material and 3-chlorobenzyl chloroformate as a protective reagent according to the operation of example 2; then, by following the procedure of example 4, 13-O- { (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7-O- (3-chlorobenzyloxycarbonyl) -baccatin III (Compound 7) was obtained.
ESI-MS[M]+＝1139.46。
Using baccatin III as a raw material and 4-chlorobenzyl chloroformate as a protective reagent, according to the operation of the embodiment example 2, 7-O- (4-chlorobenzyloxycarbonyl) -baccatin III is prepared; then, by following the procedure of example 4, 13-O- { (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7-O- (4-chlorobenzyloxycarbonyl) -baccatin III (Compound 8) was obtained.
ESI-MS[M]+＝1139.52。
Preparation of the Compound of formula 2
Example 5
Preparation of 7, 10-O-dibenzyloxycarbonyl docetaxel
13-O- { (4S, 5R) -3-tert-Butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7, 10-O-dibenzyloxycarbonyl-10-deacetylbaccatin III (compound 1, 5g, 4.2 mmol) was dissolved in acetic acid (20mL) at room temperature, trifluoroacetic acid (3mL) was added and water (3mL) was added slowly dropwise. After the addition was complete, the reaction was carried out at room temperature and monitored by HPLC. After completion of the reaction, water (70mL) was further added to the reaction mixture to precipitate a white solid, which was then filtered. The filter cake was washed with cold water (30 ml. times.2) and dried under reduced pressure in vacuo to give the title compound as a white solid (4.2 g) in 94% yield.
ESI-MS[M]+＝1075.51。
Example 6
Preparation of 2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] -7, 10-O-dibenzyloxycarbonyloxetaxel hydrochloride
1) Preparation of 4-N, N-dimethylamino-2 (R) -fluorobutyryl chloride hydrochloride: in a flask, 4-N, N-dimethylamino-2 (R) -fluorobutyric acid hydrochloride (1.67g, 9mmol) was added to thionyl chloride (10ml), and slowly heated to 40 ℃ for reaction for 4 hours. Thionyl chloride was removed by evaporation under reduced pressure, anhydrous dichloromethane (25ml) was added, the solvent was removed by evaporation under reduced pressure, and anhydrous dichloromethane (60ml) was added to the residue for further use.
2) 7, 10-O-dibenzyloxycarbonyloxetaxol (2.2g, 2mmol) and 4-N, N-lutidine (1.4g, 11.5mmol) were added to anhydrous dichloromethane (150ml) at-50 ℃ and dissolved with stirring. Slowly adding the dichloromethane solution of the 4-N, N-dimethylamino-2 (R) -fluorobutyryl chloride hydrochloride prepared in the step 1) dropwise, and detecting the reaction by HPLC. After completion of the reaction, the dichloromethane layer was washed with saturated aqueous sodium chloride solution (pH adjusted to about 2.0 with hydrochloric acid), the organic layer was dried over anhydrous sodium sulfate, filtered, dichloromethane was removed by rotary evaporation, and the residue was crystallized from acetone and methyl tert-butyl ether to give the title compound 2.16g as a white solid in 85% yield.
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。
Example 7
Preparation of 2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] docetaxel hydrochloride
2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] -7, 10-O-dibenzyloxycarbonyloxetaxelHCl hydrochloride (1.25g, 1mmol) was dissolved in anhydrous tetrahydrofuran (30ml) at room temperature, and 10% Pd/C (120mg) was added. After the gas was replaced with nitrogen, hydrogen gas was introduced and the reaction was carried out at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was diluted with anhydrous tetrahydrofuran (20ml), filtered, and the solvent was removed from the cake by concentration under reduced pressure to obtain 0.88g of the title compound as a white solid in a yield of 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。
Example 8
Preparation of 7-O-benzyloxycarbonyl paclitaxel
13-O- { (4S, 5R) -3-benzoyl-2- (4-methoxyphenyl) -4-phenyl-5-oxazolidine } formyl-7-O-benzyloxycarbonyl-baccatin III (compound 6, 4g, 3.6mmol) was dissolved in acetic acid (22 mL) at room temperature, trifluoroacetic acid (5mL) was added, and water (3mL) was slowly added dropwise. After the addition was complete, the reaction was monitored by HPLC. After completion of the reaction, water (50mL) was added to the reaction, a white solid precipitated, which was filtered, and the cake was washed with cold water (25mL × 2), and then dried under reduced pressure in vacuo to obtain the title compound as a white solid (3.4 g) in a yield of 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.
Example 9
Preparation of 2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] -7-O-benzyloxycarbonyl taxol hydrochloride
1) Preparation of 4-N, N-dimethylamino-2 (R) -fluorobutyryl chloride hydrochloride: in a flask, 4-N, N-dimethylamino-2 (R) -fluorobutyric acid hydrochloride (1.67g, 9mmol) was added to thionyl chloride (10m 1), and slowly heated to 40 ℃ for 4 hours. Thionyl chloride was removed by evaporation under reduced pressure, anhydrous dichloromethane (25ml) was added, the solvent was removed by evaporation under reduced pressure, and anhydrous dichloromethane (60ml) was added to the residue for use.
2) 7-O-benzyloxycarbonyltaxol (2.2g, 2.2mmol) and 4-N, N-lutidine (1.4g, 11.5mmol) were added to anhydrous dichloromethane (150ml) at-50 ℃ and dissolved by stirring. Slowly adding the dichloromethane solution of the 4-N, N-dimethylamino-2 (R) -fluorobutyryl chloride hydrochloride prepared in the step 1) dropwise, and detecting the reaction by HPLC. After completion of the reaction, the dichloromethane layer was washed with saturated aqueous sodium chloride solution (pH adjusted to about 2.0 with hydrochloric acid), the organic layer was dried over anhydrous sodium sulfate, filtered, dichloromethane was removed by rotary evaporation, and the residue was crystallized from acetone and methyl tert-butyl ether to give the title compound 2.05g as a white solid in 80% yield.
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。
Example 10
Preparation of 2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] taxol hydrochloride
2' -O- [4-N, N-dimethylamino-2 (R) -fluorobutyryl ] -7-O-benzyloxycarbonyl taxol hydrochloride (1.30g, 1.1mmol) was dissolved in anhydrous tetrahydrofuran (30ml) at room temperature, and 10% Pd/C (130mg) was added. After the gas was replaced with nitrogen, hydrogen was introduced and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with anhydrous tetrahydrofuran (20ml), filtered, and the solvent was removed from the cake by concentration under reduced pressure to obtain 1.05g of the title compound as a white solid in 91% yield.
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 (14)
1. A process for preparing a compound of formula 2:
wherein:
R1is tert-butoxy or phenyl;
R2is H or acetyl;
x is H, C1-6Alkyl or F;
y is F or C substituted by one or more F1-6An alkyl group;
n is 1, 2, 3, 4, 5 or 6;
w is NR5R6A or
R5、R6Each independently H, C optionally substituted by phenyl1-6Alkyl, or C3-6A cycloalkyl group;
m is 0, 1, 2 or 3; and is
A is a pharmaceutically acceptable acid, and A is a pharmaceutically acceptable acid,
the method is characterized in that: preparing the compound of formula 2 from a compound of formula 1:
wherein:
R1as defined for the compound of formula 2;
R2when is H, R3Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one halogen;
R2when it is acetyl, R3Is acetyl; and is provided with
R4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one halogen.
2. The method of claim 1, wherein: when R is2When is H, R3Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one chlorine.
3. The method of claim 2, wherein: r3Is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
4. The method of claim 1, wherein: r is4Is benzyloxycarbonyl, optionally substituted by one chlorine, or allyloxycarbonyl.
5. The method of claim 4, wherein: r4Is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
6. The method of any of claims 1-5, wherein: the compound of formula 2 is prepared via the following reaction scheme 1 starting from the compound of formula 1:
reaction scheme 1
Wherein R is1、R2、R3、R4W, X, Y and n are as defined in claim 1; and is
G is halogen or hydroxy.
7. The method of claim 6, wherein: g is chlorine, bromine or hydroxyl.
8. A compound of formula 1:
wherein the content of the first and second substances,
R1is tert-butoxy or phenyl;
R3is acetyl, benzyloxycarbonyl optionally substituted with one halogen, or allyloxycarbonyl; and is
R4To be optionally coveredA halogen-substituted benzyloxycarbonyl group, or an allyloxycarbonyl group.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: r3Is acetyl, benzyloxycarbonyl optionally substituted with one chlorine, or allyloxycarbonyl.
10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: r is3Acetyl, benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: r is4Is benzyloxycarbonyl, or allyloxycarbonyl, optionally substituted with one chlorine.
12. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein: r is4Is benzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl or allyloxycarbonyl.
13. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, selected from:
14. a process for preparing a compound of formula I,
the method is characterized in that: the compounds of formula 1 are prepared via the following reaction scheme 2:
reaction scheme 2
Wherein R is1、R2、R3、R4As defined in claim 1.
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