CN113372305B

CN113372305B - Preparation method of eribulin intermediate

Info

Publication number: CN113372305B
Application number: CN202010179520.9A
Authority: CN
Inventors: 王小龙; 蒋晓龙; 周建; 穆灿灿; 叶家海
Original assignee: Nanjing Shengding Pharmaceutical Technology Co ltd
Current assignee: Nanjing Shengding Pharmaceutical Technology Co ltd
Priority date: 2020-03-09
Filing date: 2020-03-09
Publication date: 2022-10-18
Anticipated expiration: 2040-03-09
Also published as: WO2021179683A1; CN113372305A

Abstract

The invention provides a preparation method of eribulin intermediate, which comprises the following steps: (1) Combining formula (I)The compound is reacted with (2- (R substituted oxy) ethyl) triphenyl phosphonium bromide in tetrahydrofuran solvent to be transformed into a formula (II); (2) Compounds of formula (II) in Pd (OH) ₂ Carrying out reduction reaction at the temperature of/C to obtain a compound shown in a formula (III); (3) The compound of the formula (III) is subjected to ring opening under the conditions of titanium tetrachloride and allyl trimethyl silane to generate a compound of a formula (IV); (4) The compound of the formula (IV) is oxidized to generate a compound of a formula (V) under the condition of a dessimutane oxidant; (5) Formula (V) in MePPh ₃ Br and potassium tert-butoxide to produce a compound of formula (VI) (6) and a compound of formula (VI) and addition reaction is carried out under the conditions of borane, 2-methyl-2-butene and sodium borate to produce a compound of formula (VII). The method for preparing the eribulin intermediate has the advantages of easily available raw materials, mild reaction conditions in each step, easiness in purification, simplicity in operation and higher yield.

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 an eribulin intermediate.

Background

In 1985, uemura et al isolated a polyether macrolactone from the scarce sponge Halichondria okadai in Japan, and named halichondrin B (halichondrin B). Biological experiments show that the halichondrin B has a strong inhibiting effect on cancer cells in vivo and in vitro of mice. Halichondrin B contains 32 chiral molecules and is difficult to synthesize.

In recent years, eribulin compound (formula 1) which is a macrocyclic ketone structure and has a remarkable treatment effect on metastatic breast cancer is obtained by continuously optimizing the structure of halichondrin B. Currently, eribulin mesylate injection is marketed in a number of countries.

The eribulin structure contains 19 chiral carbon molecules, and the synthesis and preparation routes are complex.

Therefore, the research finds that eribulin is an important intermediate (VII), which is particularly important for eribulin synthesis.

R substituents include, but are not limited to: piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz, allyl

Disclosure of Invention

The technical problem to be solved by the invention is to provide a synthetic route, which has the advantages of easily obtained raw materials, mild reaction conditions in each step, easy purification, simple operation and higher yield.

In order to achieve the purpose of the present invention, the present inventors finally obtained the following technical solutions through a large number of experimental reaction studies:

Detailed Description

In order to more clearly understand the present invention, we further illustrate in connection with the reaction example:

1. (II) Synthesis: 22.7g (2- (pivaloyloxy) ethyl) triphenyl phosphonium bromide is added into a three-neck flask, 120ml tetrahydrofuran is added and stirred, nitrogen is protected, cooling is carried out in ice bath, 5.4g potassium tert-butoxide dissolved in 20ml tetrahydrofuran is added dropwise. The resulting mixture was stirred at this temperature for 1h. A solution of 3.2g of compound (I) in 20ml of THF is slowly added dropwise. The reaction was stirred at room temperature for 5h until the reaction was complete as monitored by HPLC. The reaction mixture was extracted three times with 200ml of saturated brine and 50ml of 3 ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure (28-34 ℃ C.), and eluted with silica gel column chromatography (PE: EA = 10: 0 to 20: 1) to give 3.1g of a pale yellow oily liquid with a yield of 91.1%.

2. (III) Synthesis: a clean 100ml single-neck flask was taken, 3.1g of compound (II), 30ml of isopropyl alcohol were added, and 155mg of Pd (OH) was added thereto ₂ C (wet, 60% water), lower chamber of the mixture obtained in hydrogen atmosphere (balloon hydrogenation)The reaction was stirred gently (18-22 ℃) for 10-16h until the reaction was complete as monitored by GC. The reaction mixture was filtered through Celite, and the filtrate was spin-dried under reduced pressure (28-34 ℃ C.), and the crude product obtained was subjected to silica gel column chromatography (PE: EA = 50: 0 to 50: 6) to give 2.9g of a colorless oily liquid with a yield of 92.4%.

3. (IV) Synthesis: a clean 250mL three-necked flask was charged with 8g TiCl ₄ Adding 45mL of dichloromethane for dissolution, placing the mixture in an ice bath for cooling and stirring under the protection of nitrogen, and dropwise adding 4.0g of Ti (O-iPr) into the mixture at the temperature of less than 5 ℃ of internal temperature ₄ After the completion of the dropwise addition, the reaction system was stirred in an ice bath for 1 hour, a 45mL dichloromethane solution of 6.7g of compound (IV) and 5.3g of allyltrimethylsilane was added dropwise thereto, and the resulting mixture was stirred in the ice bath for about 3 hours until the reaction was completed as monitored by GC. The reaction was quenched with 30mL 1N HCl and stirred in an ice bath for 15min. The layers were separated and the aqueous layer was extracted three times with 50mL of dichloromethane, the organic layers were combined and 50mL of saturated NaHCO was used ₃ Washing, 50mL of saturated brine, drying the organic phase with anhydrous sodium sulfate, filtering, spin-drying the filtrate under reduced pressure (28-34 ℃), and subjecting the resulting crude product to silica gel column chromatography (PE: EA = 10: 0 to 4: 1) to obtain 5.8g of a colorless oily liquid with a yield of 90.9%.

4. (V) Synthesis: a clean 100mL three-necked flask was taken, 5.3g of compound (IV) was added, 50mL of DCM was added and dissolved, cooled in an ice bath under nitrogen protection, and 16.0g of Dess-Martin reagent was added thereto. The resulting mixture was gradually warmed to room temperature and stirred (18-22 ℃) for 12-16h until the reaction was complete as monitored by GC. The reaction was cooled in an ice bath, quenched by the addition of 100mL saturated sodium thiosulfate and 100mL saturated sodium bicarbonate, separated, the aqueous phase extracted with 50mL DCM, the combined organic layers washed with 50mL saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin dried under reduced pressure (28-34 ℃). Silica gel column chromatography (PE: EA = 10: 0 to 4: 1) gave 4.8g of a pale yellow oily liquid with a yield of 91.4%.

5. (VI) Synthesis: a clean 100ml three-neck flask was taken and 17.6g MePPh were added ₃ Br and 5.54g of potassium tert-butoxide under nitrogen protection. The mixture was cooled in an ice bath, to which 50ml tetrahydrofuran was slowly added. The resulting mixture was stirred at this temperature for 1h. A solution of 3.5g of compound (V) in 15ml of THF is slowly added dropwise (dropwise over 20 min). The reaction solution was dissolved in iceThe bath was stirred for 1 hour until the reaction was complete as monitored by GC. The reaction mixture was diluted with 120mL of ethyl acetate and washed twice with saturated brine at 50mLx 2. Dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary dried under reduced pressure (28-34 ℃). Obtaining a light yellow solid crude product. Silica gel column chromatography (PE: EA = 10: 0 to 20: 1) gave 3.0g of a pale yellow oily liquid, 86.4% yield.

6. (VII) Synthesis: under the protection of nitrogen, 7.5mL of borane in tetrahydrofuran is added into a 100mL three-necked flask and cooled in an ice bath. 1.05g of 2-methyl-2-butene in tetrahydrofuran (10 ml) was slowly added thereto. The resulting mixture was stirred at 0 ℃ for 2 hours. The temperature was lowered to-20 ℃ and half of the above mixture was slowly dropped into 10ml of a tetrahydrofuran solution containing 1.0g of the compound (VI), and the resulting mixture was stirred for 1 hour. The other half of the mixture was slowly added to the mixture and stirred at-20 ℃. After 2h, 15ml of water was slowly added to the reaction solution to quench, and the mixture was warmed to room temperature, and after 15min, 1.7g of sodium borate was slowly added thereto, and stirred for 8h. TLC monitoring, after the reaction is finished, 60ml of saturated sodium chloride solution is added for quenching, methyl tert-butyl ether (100 mlx 3) is added for extraction, the organic phases are combined, dried by anhydrous sodium sulfate, filtered, and the filtrate is dried by spin-drying under reduced pressure (28-34 ℃). Silica gel column chromatography (PE: EA = 10: 1 to 1: 5) gave 820mg of a colorless oily liquid with a yield of 75.0%.

The invention has been illustrated with the R substituent as PIV, and the other examples of R substituents operate in the same manner as the above examples. R substituents include, but are not limited to: piv, bn, PMB, bz, THP, ac, TMS, TBS, TBDPS, TES, TIPS, MOM, SEM, tr, cbz, allyl.

The foregoing shows and describes embodiments of the present invention, together with advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are given by way of illustration of the principles of the present invention, and that various changes and modifications may be made without departing from the spirit and scope of the invention as defined by the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims

1. A preparation method of eribulin intermediate is characterized by comprising the following steps:

(1) Reacting the compound shown in the formula (I) with (2- (R-substituted oxy) ethyl) triphenyl phosphonium bromide in the presence of potassium tert-butoxide at normal temperature to convert the compound into a compound shown in the formula (II):

the R substituent is Piv;

(2) The compound of the formula (II) is subjected to reduction reaction to obtain a compound of the formula (III):

the R substituent is Piv; the reduction reaction catalyst is Pd (OH) with the water content of 60 percent ₂ /C, the compound (II) with Pd (OH) ₂ The mass ratio of/C is 1: 20, the reaction temperature is 18-22 ℃, and the reaction time is 10-16h;

(3) The compound of formula (III) is subjected to ring opening under the condition of allyltrimethylsilane to generate a compound (IV):

the R substituent is Piv;

(4) Reacting the compound of the formula (IV) with Dess-Martin to generate a compound (V):

the R substituent is Piv;

(5) Reacting the compound of the formula (V) in methyl triphenyl phosphonium bromide to generate a compound (VI):

the R substituent is Piv;

(6) The compound of formula (VI) is formed into a compound (VII) under the condition of borane:

the R substituent is Piv.

2. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (1), the reaction temperature is 18-22 ℃, the reaction time is 4h, and the molar ratio of the compound (I) to the (2- (R-substituted oxy) ethyl) triphenyl phosphine bromide is as follows: 1-1, and the reaction solvent is selected from one of dichloromethane and tetrahydrofuran, wherein the R substituent is Piv.

3. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (2), the reaction solvent is selected from one of methanol and isopropanol.

4. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (3), the molar ratio of the compound (III) to titanium tetrachloride is 1.8, the molar ratio of titanium tetrachloride to allyl trimethylsilane is 0.9.

5. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (4), the reaction temperature is 0 ℃, the reaction time is 1h, and the molar ratio of the compound (IV) to the dessimutan reagent is 1:2.0, the reaction solvent is dichloromethane.

6. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (5), the reaction temperature is 0 ℃, the reaction time is 2 hours, the molar ratio of the compound (v) to potassium tert-butoxide is 1.

7. The method for preparing eribulin intermediate according to claim 1, wherein: in the step (6), the reaction temperature is-20-0 ℃, the reaction time is 20h, the molar ratio of the compound (VI) to the borane is 1.