CN118359565A - Preparation method of eribulin intermediate - Google Patents

Preparation method of eribulin intermediate Download PDF

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CN118359565A
CN118359565A CN202310061308.6A CN202310061308A CN118359565A CN 118359565 A CN118359565 A CN 118359565A CN 202310061308 A CN202310061308 A CN 202310061308A CN 118359565 A CN118359565 A CN 118359565A
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formula
compound
reaction
eribulin intermediate
eribulin
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王小龙
吉海峰
蒋晓龙
周建
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Nanjing Shengding Pharmaceutical Technology Co ltd
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Nanjing Shengding Pharmaceutical Technology Co ltd
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Abstract

The invention provides a novel eribulin intermediate and a synthesis method of the intermediate, wherein the intermediate can be used for conveniently synthesizing an intermediate A, and the eribulin intermediate has the following structure

Description

Preparation method of eribulin intermediate
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of eribulin intermediates.
Background
In 1985, uemura et al isolated a polyether macrolide from Japanese scarce sponge Halichondria okadai, designated halichondrin B (halichondrin B). Biological experiments show that the halichondrin B has a strong inhibition effect on cancer cells in and out of mice. Halichondrin B contains 32 chiral molecules and is difficult to synthesize.
In recent years, the structure of halichondrin B is continuously optimized to obtain an eribulin compound which is a macrocyclic ketone structure and has remarkable treatment effect on metastatic breast cancer. Currently, eribulin mesylate injection has been marketed in several countries.
The eribulin structure contains 19 chiral carbon molecules, and the synthetic and preparation routes are relatively complex.
Therefore, researchers research and find that an important intermediate A of eribulin has the following structure, and is particularly important for the synthesis of eribulin:
Wherein the R substituents include, but are not limited to: piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl.
Chinese patent CN113372305A filed earlier by the present inventors discloses a method for synthesizing the above intermediate, the synthetic route of which is shown as follows:
The reaction route is mild in condition, but the following problems still exist in mass production:
1. in the reaction of the formula (VI) to prepare the product intermediate (VII) by hydroboration-oxidation, the formula (VI) has two double bonds, and the selectivity of the selective oxidation chain end double bond is relatively high under the laboratory condition, but the selectivity is poor with the enlargement of the production scale, so that the impurity content of the product, which is composed of byproducts obtained by simultaneously oxidizing the two double bonds and independently oxidizing the five-membered ring double bond, is obviously increased.
2. In the reaction of preparing the product intermediate (VII) by hydroboration of the formula (VI), the requirement on the feeding amount of the hydroboration reagent is very high, if the feeding amount of the hydroboration reagent is insufficient, a lot of raw materials are not reacted and remain, in order to ensure the full reaction of the raw materials, the hydroboration reagent always needs to be excessively fed, but excessive feeding generates impurities of two double bonds oxidized simultaneously, so that the excessive degree is very difficult to control, and the error and the control difficulty are larger in large-scale production.
3. In the reaction of preparing the product intermediate (VII) from the formula (VI) through hydroboration oxidation, impurities and products are similar in structure, are high-polarity substances, and have high separation cost and difficulty. The above disadvantages become more evident in large-scale production, making the process stability poor and the yield difficult to guarantee.
Disclosure of Invention
In view of this, the present invention provides a novel eribulin intermediate, through which intermediate a can be synthesized conveniently, and a method for synthesizing the intermediate.
The invention provides an eribulin intermediate, which has a structure shown in a formula V: Wherein R 1、R2 is a hydroxyl protecting group selected from Piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl;
Wherein the reaction conditions for deprotection of the R 1 and R 2 groups are different, preferably the reaction conditions for deprotection of the R 1 and R 2 groups are different and are each basic or acidic, preferably the deprotection conditions for R 1 are basic, the deprotection conditions for R 2 are acidic, most preferably R 1 is Piv, and R 2 is Tr.
The invention provides a preparation method of an eribulin intermediate, which has a structure shown in a formula V: Wherein R 1、R2 is a hydroxyl protecting group selected from Piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl;
Wherein the reaction conditions for deprotection of the R 1 and R 2 groups are different, preferably, the reaction conditions for deprotection of the R 1 and R 2 groups are respectively alkaline and acidic, preferably, the deprotection condition of R 1 is alkaline, the deprotection condition of R 2 is acidic, most preferably, R 1 is Piv, and R 2 is Tr. The definitions of R 1 and R 2 described above apply equally to the starting materials used in the steps described below and to the intermediates synthesized.
The method is characterized by comprising the following steps of:
Step one:
The compound of the formula I is subjected to hydroboration-oxidation reaction to prepare the compound of the formula II,
The compounds of formula I can be prepared by the methods disclosed by, for example, CN113372305A by converting the hydroxy protecting group;
the borane reagent used in the hydroboration reaction can be any commonly used borane, and in-situ generated deactivation borane reagents such as borane, diborane, C1-4 alkyl boron, 9-BBN, and in-situ generated deactivation borane reagents such as borane and 2-methyl-2-butene; the oxidant of the oxidation reaction is selected from peroxides, preferably sodium perborate, hydrogen peroxide, peracetic acid, sodium percarbonate, peroxyphosphoric acid or m-chloroperoxybenzoic acid.
The solvent used in the hydroboration-oxidation reaction is a nonpolar aprotic organic solvent, preferably tetrahydrofuran or diethyl ether.
When the borane reagent is a mono-borane type borane reagent, the molar ratio of the borane reagent to the compound of formula I is not less than 3-4, preferably not less than 3, most preferably not less than 4.
Step two:
Hydroxyl protecting reaction is carried out on chain segment hydroxyl of the compound of the formula II to obtain the compound of the formula III,
When R 2 is Tr, the compound of formula II is reacted with Ph 3 CCl to provide the compound of formula III.
In this step, the inventors found that the protecting group reagent would preferentially react with the hydroxyl group at the chain end, and the protection of the hydroxyl group is achieved, probably because the hydroxyl group at the chain end is a primary alcohol, the hydroxyl group on the five-membered ring is a secondary alcohol, and the steric hindrance of the primary alcohol is smaller than that of the secondary alcohol.
Step three:
oxidizing the compound of formula III to obtain a compound of formula IV,
The oxidation reaction may be carried out in the presence of an oxidizing agent by any known oxidation reaction to convert the compound of formula III to a compound of formula IV, preferably by reacting the compound of formula III with a Dess-Martin reagent to give a compound of formula IV;
Step four:
Carrying out alkenyl reaction on the compound of the formula IV to obtain a compound of the formula V,
The compound of formula IV can be converted to the compound of formula V using any known reaction type, preferably using a Wittig reaction, the Wittig reagent of which is preferably MePPh 3 Br/potassium tert-butoxide.
The invention further provides a preparation method of the eribulin intermediate A, wherein the eribulin intermediate A has a structure shown in a formula VI:
is characterized in that the compound of the formula V is selectively dehydroxylated for protection to obtain the compound of the formula VI,
Wherein R 1、R2 is a hydroxyl protecting group selected from Piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl;
wherein the reaction conditions for deprotection of the R 1 and R 2 groups are different, preferably, the reaction conditions for deprotection of the R 1 and R 2 groups are respectively alkaline and acidic, preferably, the deprotection condition of R 1 is alkaline, the deprotection condition of R 2 is acidic, most preferably, R 1 is Piv, and R 2 is Tr.
The removal conditions for R 1 and R 2 of the compound of formula V are different, and in this case, the removal conditions suitable for R 2 may be selected to selectively remove R 2 to obtain the compound of formula VI, for example, when R 2 is Tr and R 1 is Piv, since Tr may be selectively removed under acidic conditions and Piv is removed under basic conditions, the compound of formula V is hydrolyzed under acidic conditions to selectively remove R 2, but R 1 is not removed, thereby obtaining the compound of formula VI wherein R 1 is Piv.
According to the technical scheme, compared with the scheme of CN113372305A, the double bond selectivity problem faced by the borohydride-oxidation reaction is avoided by advancing the borohydride-oxidation reaction to the oxidation reaction (Dess-Martin reaction), and the borohydride reagent can be excessively added to a large extent in the step of reaction, so that the reactant is ensured to be completely converted, and the byproduct impurities are not required to worry, thereby greatly reducing the operation difficulty in industrial production and improving the yield of the whole reaction.
The advanced hydroboration-oxidation reaction, although adding a hydroxyl protection step, has been found by the present invention that the selectivity of the hydroxyl protection is higher, especially the selectivity of Ph 3 CCl is very high, and the conditions for removing Tr groups and most commonly the Piv groups of intermediate a where R 1 is Piv are exactly opposite, enabling convenient and highly selective removal to give the desired intermediate a.
The impurities in each step of the reaction are less, the separation difficulty and the cost are obviously reduced, and the method is more suitable for industrial production.
Detailed Description
For a clearer understanding of the invention, we further describe in connection with the reaction examples:
Example 1-1: synthesis (laboratory Process) of a Compound of formula II (R 1 is Piv)
4 Equivalents of BH 3 -THF solution are introduced into a three-necked flask, protected by nitrogen, placed in an ice bath, mechanically stirred and cooled, and 8.0 equivalents of 2-methyl-2-butene are slowly added dropwise thereto. The obtained mixture is placed in an ice bath and stirred for 2 to 2.5 hours. Another four-necked flask was taken, 1 equivalent of a 3-4V THF solution of the compound of formula I (R 1: piv) was added thereto, and the flask was placed in a dry ice-ethanol bath under nitrogen atmosphere with mechanical stirring to control the internal temperature. Half of the boron reagent is dripped into a four-necked flask, and the reaction solution is stirred at a low temperature for 1 hour after the dripping is finished. Then, the remaining half of the boron reagent was dropped into the four-necked flask, and the reaction solution was stirred at a low temperature for 2 hours after the completion of the dropping. After completion of the TLC control reaction, 7.5V water was added dropwise to the reaction mixture, the mixture was stirred at room temperature for 30 minutes, 6 equivalents of NaBO 3·4H2 O were added to the reaction mixture, the resulting mixture was stirred at room temperature, and after completion of the TLC control reaction, 5.5V MTBE was added for dilution and separation. The aqueous layer was extracted with 3.4VMTBE, the organic phases were combined, the brine layer was washed with saturated brine, the brine layer was extracted with MTBE, the organic phases were combined, dried over anhydrous Na 2SO4, filtered, the filtrate was dried under reduced pressure to give a colorless oily liquid, the target component was collected by silica gel column chromatography, and the colorless oily liquid was obtained by drying under reduced pressure. The results of the three different dosing experiments are shown in table 1:
Batch of Feeding quantity (g) Weight of product (g) Purity (%)
1 147.2 146.8 84.3％
2 368 361 85.2％
TABLE 1
Examples 1-2: synthesis (amplification Process) of Compound of formula II (R 1 is Piv)
After blowing the dry and clean 200L enamel reaction kettle with N 2 for 5-10min, pressing 77.53kg BH 3 -THF under the protection of N 2, stirring and cooling to-5-5 ℃, beginning to dropwise add 13.23kg 2-methyl 2-butene, and stirring at-5-5 ℃ for 1-1.5h after the dropwise addition. Adding 27.7kg of THF and 9.1kg of a compound shown as a formula I (R 1 is Piv) into another 200L enamel reaction kettle, stirring and dissolving, cooling to-25 ℃ to-15 ℃ under the protection of N 2, slowly pressing the prepared boron reagent into the 200L enamel reaction kettle, stirring for 1.5-2h at-25 ℃ to-15 ℃ after the addition is completed, dropwise adding 54.6kg of water after the TLC central control reaction is completed, stirring for 30min after the dropwise adding is completed, controlling the temperature to 25-35 ℃, adding 35.88kg of sodium perborate tetrahydrate in batches, stirring for 10-14h at 25-30 ℃ after the addition is completed, and performing HPLC central control reaction completely. After standing, the mother liquor was filtered, and the organic phase was separated, washed once with 33L of saturated saline and once with 16.5L of saturated saline. Spin-drying gave 9.82kg of a pale yellow oil, 85.7% pure.
Example 2-1: synthesis (laboratory Process) of a Compound of formula III (R 1 is Piv and R 2 is Tr)
1 Equivalent of the compound of formula II (R 1 as Piv) was added to a three-necked flask, dissolved in DCM (5V), and then added with 1.8 times equivalent of triethylamine and 0.05-0.1 times equivalent of DMAP under nitrogen, and magnetically stirred. The reaction system is placed in an ice salt bath for cooling (the internal temperature is less than or equal to minus 5 ℃). Dropwise adding 1.05 times equivalent of DCM (5V) solution of Ph 3 CCl (internal temperature is less than or equal to minus 5 ℃) into the solution, gradually heating the obtained reaction mixture to room temperature, stirring, placing a reaction bottle in an ice bath for cooling after the reaction is monitored to be complete by HPLC, dropwise adding saturated NaHCO 3 into the reaction bottle for quenching the reaction, stirring, separating liquid, washing an organic phase with saturated common salt, drying the organic phase with anhydrous sodium sulfate, filtering, carrying out reduced pressure spin-drying on the filtrate to obtain yellow oily liquid, carrying out silica gel column chromatography elution, collecting target components, and carrying out reduced pressure spin-drying to obtain light yellow oily liquid. The results of the three different dosing experiments are shown in table 2:
Batch of Feeding quantity (g) Weight of product (g) Yield (%) Purity (%)
1 50.0 77.6 84.3％ 97.84％
2 127.0 207.7 88.9％ 97.83％
3 156.0 245.0 85.3％ 95.68％
TABLE 2
Example 2-2: synthesis (amplification Process) of a Compound of formula III (R 1 is Piv and R 2 is Tr)
9.88Kg of the compound of the formula II (R 1 is Piv), 50kg of methylene chloride, 5.21kg of triethylamine, 50g of DMAP and cooling to-5-5 ℃ are added in a dry and clean 200L reaction kettle under the protection of N 2. After the completion of the reaction by HPLC detection, 20kg of water is added, the mixture is stirred for 20 to 30min to separate the liquid, and the organic layer is concentrated under reduced pressure to dryness to obtain 21.0kg of crude light yellow oily product. Column chromatography gave 11.9kg of pale yellow oil, 95.3% pure, 1.05% isomer.
Example 3-1: synthesis (laboratory Process) of a Compound of formula IV (R 1 is Piv and R 2 is Tr)
The compound of formula III (R 1 is Piv and R 2 is Tr) (1 eq.) was dissolved in DCM (10V), placed in a three-necked flask, cooled in an ice bath, mechanically stirred, nitrogen-protected, and Dess-Martin reagent (2 eq.) was added thereto, maintaining an internal temperature of 3-8 ℃. The resulting mixture was gradually warmed to room temperature and stirred, after completion of the reaction by HPLC monitoring, the reaction mixture was cooled in an ice bath, saturated sodium thiosulfate (4V) and saturated sodium bicarbonate (4V) were added thereto to quench the reaction, the resulting mixture was warmed to room temperature and stirred for 1 hour, the liquid was separated, the aqueous layer was extracted with DCM (7.5 v×2), the organic phases were combined, washed with saturated sodium thiosulfate, washed with saturated sodium bicarbonate, and washed with saturated brine. Drying anhydrous sodium sulfate, filtering, decompressing and spin-drying filtrate to obtain yellow oily liquid, and directly throwing the yellow oily liquid into the next step, wherein experimental results of four different feeding amounts are shown in table 3:
Batch of Feeding quantity (g) Weight of product (g) Yield (%) Purity (%)
1 115.5 114.3 99.3％ 96.29％
2 207.0 201.8 97.9％ 98.92％
TABLE 3 Table 3
The above yields are all crude yields, and thus may be greater than 100%, as follows.
Example 3-2: synthesis (amplification Process) of a Compound of formula IV (R 1 is Piv and R 2 is Tr)
11.6Kg of the compound of the formula III (R 1 is Piv, R 2 is Tr), 69.6kg of methylene chloride, 5.50kg of sodium bicarbonate and cooling to-5-5 ℃ are added into a dry and clean 100L reaction kettle. 13.86kg of Dess-Martin reagent is added in batches, stirring is completed for 3-4 hours, the reaction is detected by HPLC, 16.1L of saturated sodium bicarbonate solution is dripped, 21L of saturated sodium thiosulfate solution is dripped after dripping, stirring is completed after dripping, filtering is performed, and a filter cake is rinsed with 28kg of dichloromethane. The filtrate was separated, and the organic phase was washed once with 14L of saturated sodium bicarbonate and once with 14L of saturated brine. The organic phase was dried by spin-drying at 30-40℃to give 11.2kg of a pale yellow oil in 96.1% yield and 94.3% purity.
Example 4-1: synthesis of Compound of formula V (R 1 is Piv and R 2 is Tr) (laboratory Process)
MePPh 3 Br (3 eq) was dissolved in tetrahydrofuran (3V) and placed in a three-necked flask under nitrogen protection with mechanical stirring. The reaction system was cooled in an ice water bath, keeping the internal temperature <5 ℃. To this was slowly added dropwise a solution of potassium tert-butoxide (3 eq.) in tetrahydrofuran (3V) with an internal temperature of <5 ℃. The resulting reaction mixture was stirred in an ice-water bath for 1 hour, with an internal temperature of <6 ℃. To this was slowly added a solution of the compound of formula III (R 1 is Piv and R 2 is Tr) in THF (3V) and the internal temperature was controlled to <5 ℃. After the completion of the dropping, the reaction solution was stirred in an ice-water bath for 3 hours, and the internal temperature was controlled to be <5 ℃. After the reaction is monitored to be complete by HPLC, saturated ammonium chloride (3.8V) is added dropwise into the reaction solution to quench the reaction, and the internal temperature is controlled to be less than 10 ℃. After the completion of the dropwise addition, the mixture was diluted with methyl tert-butyl ether (4.8V) and n-hexane (2.8V), stirred, and separated. The aqueous layer was extracted with methyl tert-butyl ether (2.8v×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to give a brown yellow oily liquid. N-hexane (2.0V) was added thereto for beating, suction filtration was performed under reduced pressure, and the cake was washed with n-hexane (0.5V). The filter cake was slurried twice with n-hexane (2.0V), suction filtered under reduced pressure, and the filter cake was washed with n-hexane (0.5V). The organic phases were combined and dried under reduced pressure (28-32 ℃ C.). To obtain brown yellow oily liquid which is directly put into the next step. The results of four different dosing experiments are shown in table 4:
Batch of Feeding quantity (g) Weight of product (g) Yield (%) Purity (%)
1 114.3 103.7 91.1％ 80.70％
2 209.0 204.3 98.1％ 76.01％
TABLE 4 Table 4
Example 4-2: synthesis of Compound of formula V (R 1 is Piv and R 2 is Tr) (amplification Process)
After blowing the dry and clean 200L reaction kettle with N 2 for 5-10min, adding 30kg of THF and 10.55kg of methyl triphenylphosphine bromide under the protection of N 2, stirring and cooling to-5-5 ℃, beginning to dropwise add the prepared potassium tert-butoxide/tetrahydrofuran solution, and stirring for 1.5-2h after the dropwise addition is completed. A solution of the compound of formula IV (R 1 is Piv, R 2 is Tr) (11.15 kg) in tetrahydrofuran was added. After the dripping is finished, stirring for 2-3h at the temperature of-5-5 ℃. After the reaction was completed by HPLC, the reaction mixture was slowly added to 43.8kg of saturated ammonium chloride solution to quench the reaction, and the mixture was stirred and layered after the completion of the dropwise addition. The aqueous layer is extracted by 22kg methyl tertiary butyl ether, stirred and layered, the organic phases are combined and concentrated to dryness under reduced pressure at 30-40 ℃ to obtain a crude product of a compound of a formula V (R 1 is Piv and R 2 is Tr), 27.8L of n-heptane is added into the crude product to be pulped for 0.5-1h at 5-15 ℃ for filtering, 16.5L of n-heptane is added into a filter cake to be pulped for 0.5-1h at 5-15 ℃ for filtering, and the two pulped filtrate are combined and concentrated to dryness under reduced pressure at 30-40 ℃ to obtain a compound of a formula V (R 1 is Piv and R 2 is Tr) 11.08kg of light yellow oily substance, and the yield is 100.0 percent and the purity: 85.4%.
Example 5-1: synthesis (laboratory Process) of a Compound of formula VI (R 1 is Piv)
The compound of formula V (R 1 is Piv and R 2 is Tr) (1 equivalent) was dissolved in DCM (3V)/MeOH (1.5V), placed in a three-necked flask, and p-toluenesulfonic acid (1.2 equivalent) was added thereto and stirred, and the resulting mixture was stirred at room temperature for 6 hours. After the reaction was completed by monitoring the reaction by HPLC, the reaction solution was cooled in an ice bath, and saturated sodium bicarbonate was added dropwise to the reaction solution until ph=7 in the system. The organic solvent was removed by spin-drying under reduced pressure, the residue was extracted with methyl tert-butyl ether (1.8v.times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure (28-32 ℃) to give a yellow oily liquid, which was eluted by silica gel column chromatography, the target component was collected, and spin-dried under reduced pressure (28-32 ℃) to give a pale yellow oily liquid.
Batch of Feeding quantity (g) Weight of product (g) Yield (%) Purity (%)
1 32.9 18.3 85.9％ 93.95％
2 204.0 89.8 81.8％ 99.13％
3 300.6 140.7 87.0％ 92.37％
4 104.1 46.5 83.0％ 97.45％
Example 5-2: synthesis (amplification Process) of Compound of formula VI (R 1 is Piv)
18.73Kg of the compound of formula V, 24.8kg of methylene dichloride, 8.27kg of p-toluenesulfonic acid monohydrate and 56.19kg of methanol are added into a dry and clean 200L reaction kettle, the temperature is controlled to 15-25 ℃ and the mixture is stirred for 4-6 hours, 53kg of saturated sodium bicarbonate solution is added after the reaction is completed, the pH value is regulated to be 7-8, the mixture is stirred for 30 minutes, the mixture is dried in a spinning way, 38kg of MTBE is added to extract the water phase twice, the organic phase is combined, 26kg of saturated saline is used for washing the organic phase once, liquid separation and evaporation are carried out, and the light yellow 11.2kg of crude product of the compound of formula VI is obtained. Column chromatography gave 7.7kg of VI compound, 94.16% pure, isomer 2.26. Yield: 76.14% the invention is illustrated with R 1 as Piv and R 2 as Tr, and other examples of R 1、R2 substituents are operated in the same manner as described above. R 1、R2 substituents include, but are not limited to: piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl, provided that the reaction conditions for deprotection of the R 1 and R 2 groups are different to meet the goal of selective removal.
The above examples show that the process of the present invention has the yield and purity basically the same as those of laboratory process and is suitable for industrial production.
The foregoing shows and describes specific embodiments of the present invention and advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the foregoing embodiments, which are described in the foregoing description merely illustrative of the principles of the present invention, and that various changes and modifications may be made therein without departing from the spirit and scope of the invention, which is defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (16)

1. A method for preparing an eribulin intermediate, wherein the eribulin intermediate has a structure shown in formula v: Wherein R 1、R2 is a hydroxyl protecting group, wherein the reaction conditions for deprotection of the R 1 and R 2 groups are different,
The method is characterized by comprising the following steps of:
Step one:
The compound of the formula I is subjected to hydroboration-oxidation reaction to prepare the compound of the formula II,
Step two:
Hydroxyl protecting reaction is carried out on chain segment hydroxyl of the compound of the formula II to obtain the compound of the formula III,
Step three:
oxidizing the compound of formula III to obtain a compound of formula IV,
Step four:
Carrying out alkenyl reaction on the compound of the formula IV to obtain a compound of the formula V,
2. The method for preparing eribulin intermediate according to claim 1, wherein: the reaction conditions for deprotection of the R 1 and R 2 groups are different and are each basic or acidic, preferably the deprotection conditions for R 1 are basic and the deprotection conditions for R 2 are acidic.
3. The method for preparing eribulin intermediate according to claim 1, wherein: each R 1、R2 is independently selected from Piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl.
4. A process for the preparation of eribulin intermediate according to claim 3, wherein: r 1 is Piv and R 2 is Tr.
5. The method for preparing eribulin intermediate according to claim 1, wherein: in the first step, when the borane reagent is a mono-borane-type borane reagent, the molar ratio of the borane reagent to the compound of the formula I is more than or equal to 3 or more than or equal to 4.
6. The method for preparing eribulin intermediate according to claim 1, wherein: in the third step, the compound of the formula III reacts with a Dess-Martin reagent to obtain the compound of the formula IV.
7. The method for preparing eribulin intermediate according to claim 1, wherein: the compound of formula IV is converted to the compound of formula V by a Wittig reaction.
8. The method for preparing eribulin intermediate according to claim 7, wherein: the Wittig reagent of the Wittig reaction is MePPh 3 Br/potassium tert-butoxide.
9. The method for preparing eribulin intermediate according to claim 1, wherein: in the first step, the borane reagent of the borohydride-oxidation reaction is selected from borane, diborane, C 1-4 alkyl boron, 9-BBN, and deactivated borane reagent generated in situ by the above substances and 2-methyl-2-butene.
10. The method for preparing eribulin intermediate according to claim 1, wherein: in the first step, the oxidant of the hydroboration-oxidation reaction is selected from sodium perborate, hydrogen peroxide, peracetic acid, sodium percarbonate, peroxyphosphoric acid or m-chloroperoxybenzoic acid.
11. An eribulin intermediate having a structure of formula v: Wherein R 1、R2 is a hydroxyl protecting group, and the reaction conditions for deprotection of the R 1 and R 2 groups are different.
12. Eribulin intermediate according to claim 11, wherein the reaction conditions for deprotection of the R 1 and R 2 groups are different and are each basic or acidic, preferably the deprotection conditions for R 1 are basic and the deprotection conditions for R 2 are acidic.
13. The eribulin intermediate according to claim 12, wherein: each R 1、R2 is independently selected from Piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz or allyl.
14. The eribulin intermediate according to claim 13, wherein: r 1 is Piv and R 2 is Tr.
15. A preparation method of an eribulin intermediate A, wherein the eribulin intermediate A has a structure shown in a formula VI:
wherein the selective dehydroxylation of a compound of formula V according to any one of claims 11 to 13 gives a compound of formula VI,
16. The method for preparing eribulin intermediate a according to claim 15, wherein: the compound of formula v is prepared by the process of any one of claims 1-10.
CN202310061308.6A 2023-01-19 2023-01-19 Preparation method of eribulin intermediate Pending CN118359565A (en)

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