Method for preparing eribulin mesylate
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to preparation of a crude drug complex natural modified drug eribulin mesylate.
Background
Halichondrin B is a poly (poly) ether macrolide isolated from the scarce Japanese sponge Halichondriaokadai by Japanese scientist Uemura et al in the last 80 th century, and although halichondrin B only contains three elements of C \ H \ O, the compound structure is quite complex. Further research finds that the halichondrin B has very strong inhibiting effect on cancer cells in and out of a mouse body in a mouse experiment. Further research by chemists has also revealed that common sponges, such as the Phakellia, Lissodendory and Axinella families, also contain halichondrin B. The systematic activity evaluation of halichondrin B in 60 cancer cell lines by the national institute of tumor in the united states has demonstrated that halichondrin B acts in a similar mechanism to known anti-tubulin drugs in anti-cancer cell proliferation, but in a different biochemical mechanism. The halichondrin B has strong activity and unique action mechanism, so that the halichondrin B has attracted the attention of academia and the industry. However, since nature has a limit in the amount of sample extracted and separated from the sponge, development has been slow. To this end, the preparation of halichondrin B and its analogs by means of chemical synthesis has attracted extensive interest to chemists.
Halichondrin B has the following structure:
professor Kishi, Harvard university, systematically studied the total synthesis of halichondrin B and its analogs. A great deal of research has found that the lactone segment on the right of halichondrin B as shown above is a more anticancer active carrier than the polyether segment on the left, because the segment on the right contains various functional groups, and the structure of the polyether segment is monotonous. These studies have further prompted synthetic chemists to prepare a series of halichondrin B analogs for activity testing. Eribulin mesylate is one of halichondrin B analogs, eventually approved by the FDA in the united states for the treatment of metastatic breast cancer in 2010 through phase III clinical trials under the trade name HALAVENTM. The chemical structure of eribulin mesylate contains 19 chiral centers, and the chemical structural formula is as follows:
to date, a large number of patents and literature reports have been published on the preparation of eribulin mesylate. However, many documents refer to the final conversion of both hydroxyl groups of the compound to terminal amino alcohols (ERBL-07 → eribulin mesylate), and the reaction mechanism of such synthetic strategies involves the formation of an oxatricyclic intermediate (intermediate 1 and intermediate 2) followed by the opening of the amino ring. Since the ring opening of the amino group of the terminal oxatricyclic ring inevitably produces isomer impurities (isomer-1, isomer-2, isomer-3) which are similar to the product structure and are very difficult to remove in the finished product, it is crucial to develop a new synthetic strategy for successfully avoiding the production of the amino isomer impurities. The conventional synthetic route to convert the terminal dihydroxy group to an amino alcohol and some isomeric impurity structures are as follows:
disclosure of Invention
The invention aims to provide a novel method for preparing eribulin mesylate, aiming at avoiding the defect that a traditional synthetic route is easy to cause a large amount of isomer impurities.
The synthetic route of the invention is as follows:
the first step of the reaction involves the oxidation of two hydroxyl groups in the structure of N-ERBL-01 (one hydroxyl group is oxidized into a ketone carbonyl group, and the other hydroxyl group is oxidized into an aldehyde group) by using N-ERBL-01 as a starting material under the oxidation condition to obtain an N-ERBL-02 intermediate.
The oxidant used in the first step of the reaction is Dess-Martin oxidant, and the reaction solvent is dichloromethane.
The second step of the reaction involves the reaction of the N-ERBL-02 intermediate in SmI2Removing the protecting group of p-toluenesulfonyl (Ts) under the action of the N-ERBL-03 intermediate.
The third step of the reaction involves the reaction of the N-ERBL-03 intermediate in CrCl2/NiCl2In the presence of the N-ERBL-04 intermediate, the terminal alkenyl iodine reacts with aldehyde groups in molecules to prepare the N-ERBL-04 intermediate. The solvents used for this step include acetonitrile and THF.
The fourth reaction step involves the oxidation of hydroxyl to carbonyl of the N-ERBL-04 intermediate under the oxidation condition to prepare the (2- [ (2S) -2-benzoyloxy) N-ERBL-05 intermediate]-3-[(2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS)-12,13,15-
[ [ (1, 1-Dimethylethyl) dimethylsilyl group]Oxygen gas]-3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32 a-triacontahydro-3-methoxy-29-methyl-23, 30-bis (methylene) -5, 18-dioxy-7, 11:10,14:21,24:27, 31-tetracyclooxy-2H-cyclohentriacontane [ b]Furan-2-yl]Propyl radical]-1H-phthalimide). The oxidation reaction used in this step is Dess-Martin oxidation or Swern oxidation.
The fifth reaction step involves reacting the N-ERBL-05 intermediate in the presence of TBAF to produce the N-ERBL-06 intermediate (1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S) -25- [ (2S) -3-phthalimido-2-benzoyloxypropyl ] -2, 5-dihydroxy-26-methoxy-19-methyl-13, 20-dimethylene-24, 35,36,37,38, 39-hexaoxaheptacyclo [29.3.1.13,6.14,34.111,14.117,21.023,27] nonadecane-8, 29-dione).
The sixth reaction step involves reacting the N-ERBL-06 intermediate in the presence of PPTS (pyridine p-toluenesulfonate) to prepare the N-ERBL-07 intermediate (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS) -2- [ (2S) -3-phthalimide-2-benzoyloxypropyl ] -3-methoxy-26-methyl-20, 27-dimethylene hexadecahydro-11, 15:18,21:24, 28-triepoxy-7, 9-ethano-12, 15-methano-9H, 15H-furo [3,2-i ] furo [2',3', 5,6] pyran [4,3-b ] [1,4] dioxocyclopentadecanyl-5 (4H) -one).
And the seventh step of the reaction involves removing the phthalimide protecting group and the benzoyl protecting group of the N-ERBL-07 intermediate under the ammonia water condition, and then adding methanesulfonic acid to prepare eribulin mesylate.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
EXAMPLE I preparation of N-ERBL-02 intermediate
Into a four-necked flask was added N-ERBL-01 intermediate (25.00g,15.37mmol) and CH2Cl2(500mL), after stirring the supernatant, Dess-Martin oxidant (10g,23.58mmol) was added in portions. After the addition was complete, the system was stirred at room temperature to TLC to monitor the completion of the reaction of the starting material. After the reaction was complete, the system was quenched by addition of saturated aqueous sodium bicarbonate (500 mL). The system was allowed to stand and the organic phase was separated. The organic phase was stripped of organic solvent under reduced pressure at low temperature and the residue was purified by column chromatography to give N-ERBL-02 intermediate (20.23g, 81.1%).
EXAMPLE two preparation of N-ERBL-03 intermediate
Sm (13.05g,86.79mmol) was added to a four-necked bottleAnd THF (500mL) was added to the reaction mixture under stirring, and after the addition was complete, the mixture was stirred at room temperature for 5 hours. In another four-necked flask, N-ERBL-02 intermediate (15.05g,9.34mmol), methanol (200mL) and THF (500mL) were added, the system was cooled to-85 ℃ with stirring, and then the previously prepared Smi was added dropwise2And (3) solution. After the dropwise addition, the system was stirred for 4 hours until TLC confirmed that the reaction of the starting materials was complete. Adding saturated K at low temperature2CO3Aqueous solution (200mL) was quenched. TBME (1L) was added after the system was warmed to room temperature, stirred for 2 hours, and allowed to stand to separate an organic phase. The organic phase was removed under reduced pressure and the residue was purified by column chromatography to give N-ERBL-03 intermediate (10.51g, 76.7%).
EXAMPLE III preparation of N-ERBL-04 intermediate
Acetonitrile (550mL) and CrCl are added into a four-mouth bottle2(26.0g,211.55mmol) and ligand (CAS:480444-15-3,63.2g,213.24 mmol). After the addition was complete triethylamine (21.5g,212.5mmol) was slowly added dropwise with stirring. After the addition is finished, stirring for 2 hours at the temperature of 30-35 ℃, and then adding NiCl2(2.75g,21.1mmol) and stirred. A solution of the N-ERBL-03 intermediate (22.5g,15.33mmol) in THF (500mL) was then added dropwise to the reaction at room temperature. After the dropwise addition, the system is stirred for 5 hours at room temperature until the controlled raw material reaction in TLC is finished. The reaction was quenched by addition of water (300mL), the system was filtered, the filtrate was extracted three times with N-heptane, the organic phases were combined, the organic phase was removed under reduced pressure to remove the organic solvent, and the residue was purified by column chromatography to give N-ERBL-04 intermediate (15.26g, 75.0%).
EXAMPLE four N-ERBL-05 intermediate (2- [ (2S) -2-benzoyloxy]-3-[(2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS)-12,13,15-
[ [ (1, 1-Dimethylethyl) dimethylsilyl group]Oxygen gas]-3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32 a-triacontahydro-3-methoxy-29-methyl-23, 30-bis (methylene) -5, 18-dioxy-7, 11:10,14:21,24:27, 31-tetracyclooxy-2H-cyclohentriacontane [ b]Furan-2-yl]Propyl radical]-1H-phthalimide) preparation
N-ERBL-04 intermediate (11.80g,8.89mmol) and dichloromethane (150mL) were added to a four-necked flask, stirred to dissolve, and Dess-Martin oxidant (10.75g,25.35mmol) was added in portions at room temperature. And stirring the system for 2 hours after the addition is finished until the reaction of the raw materials in the TLC is finished. The system was quenched by addition of saturated aqueous sodium bicarbonate (300 mL). The system was allowed to stand and the organic phase was separated. The organic phase was stripped of organic solvent at low temperature under reduced pressure and the residue was purified by column chromatography to give N-ERBL-05 intermediate (10.66g, 90.5%).
EXAMPLE V preparation of N-ERBL-06 intermediate (1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S) -25- [ (2S) -3-phthalimido-2-benzoyloxypropyl ] -2, 5-dihydroxy-26-methoxy-19-methyl-13, 20-dimethylene-24, 35,36,37,38, 39-hexaoxaheptacyclo [29.3.1.13,6.14,34.111,14.117,21.023,27] nonadecane-8, 29-dione)
N-ERBL-05 intermediate (7.1g,5.36mmol) and THF (115mL) were added to a three-necked flask, and after stirring, imidazole (1.85g,27.18mmol) and TBAF (1M in THF,11mL) were added to the system. After the addition is finished, the system reacts at room temperature until the raw materials are completely reacted in TLC. Methanol (50mL) and 30g of resin were added, stirred for 2 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give N-ERBL-06 intermediate (4.57g, 85.5%).
Example six: N-ERBL-07 intermediate (2R, 3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS) -2- [ (2S) -3-phthalimide-2-benzoyloxypropyl ] -3-methoxy-26-methyl-20, 27-dimethylenehexadecahydro-11, 15:18,21:24, 28-triepoxy-7, 9-ethano-12, 15-methano-9H, 15H-furo [3,2-i ] furo [2',3': preparation of 5,6] pyran [4,3-b ] [1,4] dioxopentacosan-5 (4H) -one).
N-ERBL-06 intermediate (4.0g,4.01mmol) and methylene chloride (100mL) were added to a three-necked flask, and PPTS (5.6g,22.3mmol) was added to the reaction system at room temperature after dissolution with stirring. The system was stirred at room temperature for 2 hours and the TLC medium control material reaction was complete. The reaction solution was subjected to solvent removal under reduced pressure at a temperature of not higher than 15 ℃ and the residue was purified by column chromatography to give N-ERBL-07 intermediate (3.22g, 81.9%).
EXAMPLE seventhly preparation of eribulin mesylate
A three-necked flask was charged with N-ERBL-07 intermediate (2.5g,2.55mmol), isopropanol (150mL), and ammonia (250 mL). After the addition, the system was stirred at a temperature of not higher than 15 ℃ for 36 hours. TLC (thin layer chromatography) is adopted to control the raw material to completely react, the reaction solution is concentrated under reduced pressure at the temperature of not higher than 15 ℃, the residue is purified by column chromatography, the obtained free base is dissolved in acetonitrile (30mL), methanesulfonic acid (250mg) is added under stirring, the system is stirred for 10 minutes, and then the solvent is removed from the system under high vacuum at the temperature of not higher than 15 ℃ to obtain eribulin mesylate (2.06g, 95.9%).